Antihypercholesterolemic tetrazole compounds

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  and R 4  each are independently hydrogen, halogen, C 1-4  alkyl, C 1-4  alkoxy, or trifluoromethyl; 
     R 2 , R 3 , R 5  and R 6  each are independently hydrogen, halogen C 1-4  alkyl or C 1-4  alkoxy; 
     tet is ##STR2## n is an integer of from 0 to 2, inclusive; A is ##STR3## R 7  is hydrogen, C 1-4  alkyl, C 1-4  alkoxy(lower) alkyl or (2-methoxyethoxy)methyl; 
     X is --OH or ═O; and 
     R 8  is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt, 
     are novel antihypercholesterolemic agents which inhibit cholesterol biosynthesis. Intermediates and processes for their preparation are disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of our prior, co-pendingapplication Ser. No. 018,542, filed Feb 25, 1987.

BACKGROUND OF THE INVENTION

1. Field of the Invention The present invention provides novel tetrazolecompounds which are potent inhibitors of the enzmye3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and,therefore, are useful in the treatment or prevention ofhypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Thepresent invention also provides novel processes for the preparation ofthe tetrazole compounds and to certain intermediates in theirpreparation.

2. Disclosure Statement The natural Fermentation products Compactin(R=H) disclosed by A. Endo, et al. in /Journal of Antibiotics, 29,1346-1348 (1976) and Mevinolin (R=CH₃) disclosed by A. W. Alberts, etal. in J. Proc. Natl. Acad. Sci. U.S.A., 77, 3957 (1980) are very activeantihypercholesterolemic agents which limit cholesterol biosynthesis byinhibiting the enzyme HMG-CoA reductase, the rate-limiting enzyme andnatural point of cholesterogenesis regulation in mammals, including man.Compactin (R=H) and Mevinolin (R=CH₃ ; also known as lovastatin) havethe structures shown below: ##STR4##

A number of structurally related synthetic compounds useful in thetreatment of hypercholesterolemia have also been disclosed in patentsand other publications. The synthetic art most closely related is asfollows:

U.S. Pat. No. 4,198,425, issued Apr. 15, 1980 to S. Mistui, et al.describes novel mevalonolactone derivatives useful for the treatment ofhyperlipidemia and having the general formula ##STR5## wherein Arepresents a direct linkage, methylene, ethylene, trimethylene orvinylene group and R³, R⁴ and R⁵ represent various substituents.

European patent application EP-24,348 published Mar. 4, 1981 disclosesnew hypocholesterolemic and hypolipemic compounds having the structure##STR6## wherein A is H or methyl; E is a direct bond, --CH₂ --,--(CH₂)₂ --, --(CH₂)₃ -- or --CH═CH--; R¹, R² and R³ each representvarious substituents and the corresponding dihydroxy acids resultingfrom the hydrolytic opening of the lactone ring.

U.S. Pat. No. 4,375,475, issued Mar. 1, 1983 to A. K. Willard, et al.discloses essentially the same structures and is concordant to theabove-mentioned EP-24,348 patent application.

European patent application EP-68,038 published Jan. 5, 1983 disclosesand claims the resolved trans-enantiomer, process for its preparationand pharmaceutical composition thereof having the structure ##STR7## andthe corresponding dihydroxy acid, or a pharmaceutically acceptable saltthereof.

International patent application WO 84/02131 published June 7, 1984describes analogs of mevalonolactone having the structure ##STR8##wherein: one of R and R⁰ is ##STR9## and the other is primary orsecondary C₁₋₆ alkyl, C₃₋₆ cycloalkyl or phenyl-(CH₂)_(n) --;

X is --(CH₂)_(n) -- or --CH═CH--;

n is 0, 1, 2 or 3;

z is ##STR10## and R⁴, R⁵, R^(5a) and R⁶ represent various substituents.

International patent application WO 84/02903 published Aug. 2, 1984describes mevalonolactone analogs having the structures ##STR11##wherein X is --(CH₂)_(n) --, ##STR12## n=0, 1, 2, or 3 and both q's are0 or one is 0 and the other is 1 and ##STR13##

European patent application EP-142,146 published May 22, 1985 describesoxo- analogs of mevinolin-like antihypercholesterolemic agents havingthe structure ##STR14## wherein E is --CH₂ --CH₂ --, --CH═CH-- or--(CH₂)₃ --; and ##STR15## wherein the dotted lines represent possibledouble bonds there being 0, 1, or 2 double bonds.

In J. Med. Chem., 28, 347-358 (1985), G. E. Stokker, et al. report thepreparation and testing of a series of 5-substituted3,5-dihydroxypentanoic acids and their derivatives.

In J. Med. Chem., 29, 159-169 (1986), W. F. Hoffman, et al. describe thepreparation and testing of a series of 7-(substitutedaryl)-3,5-dihydroxy-6-heptenoic (heptanoic) acids and their lactonederivatives. One of the preferred compounds in the reported series hasthe structure ##STR16##

In J. Med. Chem., 29, 170-181 (1986), G. E. Stokker, et al. report thesynthesis of a series of 7-[3,5-disubstituted(1,1'-biphenyl)-2-yl]-3,5-dihydroxy-6-heptenoic acids and theirlactones. Two of the preferred compounds reported in this article havethe structures ##STR17##

U.S. Pat. No. 4,613,610, issued Sept. 23, 1986 to J. R. Wareingdescribes pyrazole analogs of mevalonolactone and its derivatives usefulfor the treatment of hyperlipoproteinemia and atherosclerosis and havingthe general formula ##STR18## wherein X is --(CH₂)_(n) --, --CH═CH--,--CH═CH--CH₂ -- or --CH₂ --CH═CH--; n is 0, 1, 2 or 3, and R¹, R², R³,R⁴, R⁵, R⁶, R⁷ and Z represent various substituents.

None of the cited patents and articles disclose or suggest thepossibility of preparing the compounds of the present invention. Theunique structural feature which incorporates a tetrazole moiety in thepresent compounds differs substantially from the cited art whileexhibiting potent HMG-CoA activity.

SUMMARY OF THE INVENTION

This invention provides novel compounds having the formula ##STR19##wherein R¹, R², R³, R⁴, R⁵ and R⁶, tet, n and A are as defined below,which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase and are useful in the treatment ofhypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Thepresent invention also provides useful intermediates, processes fortheir preparation and processes for the preparation of compounds of theFormula I.

DESCRIPTION OF THE INVENTION

The present invention provides novel tetrazole compounds which areinhibitors of the enzyme HMG-CoA reductase, which are useful in thetreatment of hypercholesterolemia, hyperlipoproteinemia andatherosclerosis, and which have the formula ##STR20## wherein R¹ and R⁴each are independently hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy ortrifluoromethyl;

R², R³, R⁵ and R⁶ each are independently hydrogen, halogen, C₁₋₄ alkylor C₁₋₄ alkoxy;

tet is ##STR21## n is an integer of from 0 to 2, inclusive; A is##STR22## R⁷ is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy(lower)alkyl or(2-methoxyethoxy)methyl;

X is --OH or ═O, and

R⁸ is hydrogen, a hydrolyzable ester group or a cation to form anon-toxic pharmaceutically acceptable salt.

This invention also provides processes for the preparation of thecompounds of Formula I and to intermediates in the preparation ofcompounds of Formula I.

The terms "C₁₋₄ alkyl", "C₁₋₆ alkyl" and "C₁₋₄ alkoxy" as used hereinand in the claims (unless the context indicates otherwise) meanunbranched or branched chain alkyl or alkoxy groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, etc.Preferably, these groups contain from 1 to 4 carbon atoms and, mostpreferably, they contain 1 or 2 carbon atoms. The term "(lower)alkyl" inthe substituent "C₁₋₄ alkoxy(lower)alkyl" as used herein and in theclaims means unbranched or branched chain alkyl groups containing from 1to 4 carbon atoms, and preferably contain 2 carbon atoms. Unlessotherwise specified in the particular instance, the term "halogen" asused herein and in the claims is intended to include chlorine, fluorine,bromine and iodine while the term "halide" as used herein and in theclaims is intended to include chloride, bromide and iodide anion. Theterm "a cation to form a non-toxic pharmaceutically acceptable salt" asused herein and in the claims is intended to include non-toxic alkalimetal salts such as sodium, potassium, calcium and magnesium, theammonium salt and salts with non-toxic amines such as trialkylamines,dibenzylamine, pyridine, N-methylmorpholine, N-methylpiperidine andother amines which have been used to form salts of carboxylic acids.Unless otherwise specified, the term "a hydrolyzable ester group" asused herein and in the claims is intended to include an ester groupwhich is physiologically acceptable and hydrolyzable under physiologicalconditions such as C₁₋₆ alkyl, phenylmethyl and pivaloyloxymethyl.

In the compounds of Formula I, it is intended that all of the doublebonds are in the trans configuration, i.e., (E), as indicated in thestructural formulae used herein and in the claims.

As the compounds of the present invention may possess one or twoasymmetric carbon atoms, the invention includes all of the possibleenantiomeric and diastereomeric forms of the compounds of Formula I asdescribed herein and in the claims. The compounds of Formula I whichcontain two centers of asymmetry may produce four possible stereoisomersdesignated as the RR, RS, SR and SS enantiomers; all four stereoisomersare considered within the scope of this invention. Specifically, thecompounds of Formula I having two asymmetric carbon atoms bearing thehydroxy groups in the 3 and 5 position may produce four possiblestereoisomers which are designated as the (3R,5S), (3S,5R), (3R,5R) and(3S,5S) stereoisomers. As used herein and in the claims, the term"(±)-erythro" is intended to include a mixture of (3R,5S) and (3S,5R)enantiomers, and the term "(±)-threo" is intended to include a mixtureof (3R,5R) and (3S,5S) enantiomers. The use of a single designation suchas ( 3R,5S) is intended to include mostly one stereoisomer. The lactoneforms of the compounds of Formula I also have two asymmetric carbonatoms at the 4 and 6 position, and the resulting four stereoisomers maybe designated as the (4R,6S), (4S,6R) (4R, 6R) and (4S,6S)stereoisomers. As used herein and in the claims, the term "trans"lactone is intended to include a mixture of (4R,6S) and (4S,6R)enantiomers while the term "cis" lactone is intended to include amixture of (4R,6R) and (4S,6S) enantiomers. Mixtures of isomers can beseparated into individual isomers according to methods which are knownper se, e.g. fractional crystallization, adsorption chromatography orother suitable separation processes. Resulting racemates can beseparated into antipodes in the usual manner after introduction ofsuitable salt-forming groupings, e.g. by forming a mixture ofdiastereoisomeric salts with optically active salt-forming agents,separating the mixture into diastereomeric salts and converting theseparated salts into the free compounds. The possible enantiomeric formsmay also be separated by fractionation through chiral high pressureliquid chromatography columns.

If it is desired to prepare the (+) isomer of the compounds of FormulaI, then the synthetic (±) isomer of the present invention may beresolved by resolution methods well-known to those skilled in the art.For example of a resolution procedure in this general class ofcompounds, U.S. Pat. No. 4,375,475 issued Mar. 1, 1983 to A. K. Willard,et al. describe the resolution of a racemic (±) trans lactone withexcess d-(+)-α-methylbenzylamine (or the corresponding1-(-)-α-methylbenzylamine), separating the resulting twodiastereoisomeric amines and hydrolyizng to the corresponding, forexample, sodium salt. The resulting salt may then be converted byconventional means to the corresponding acid, ester and lactone.Preferably, the optically active enantiomers of the compounds of FormulaI may be prepared by stereoselective synthetic procedures, some of whichare described herein. The use of optically active reagents incombination with the appropriate intermediate described herein wouldproduce the desired enantiomer of the compound of Formula I.

Since the compounds of Formula I appear to contain varying amounts ofsolvent as ascertained mainly by elemental analysis, the presentinvention is intended to include solvates of the compounds of Formula I.In some cases, it appears that the products may be true solvates, whilein other cases, the products may merely retain adventitious solvent orbe a mixture of solvate plus some adventitious solvent. Preferably, thesolvate is water and, most preferably, one to three moles of water. Theexamples below give the amount of solvent where appropriate in theanalysis and melting points are those of the solvated product unlessotherwise indicated.

In the compounds of Formula I, R¹, R², R³, R⁴, R⁵, and R⁶,independently, are preferably hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄alkoxy. More preferably, R¹ and R⁴ are hydrogen and R², R³, R⁵ and R⁶,independently, are hydrogen, fluoro, chloro, methyl or methoxy, and mostpreferably, R¹ and R⁴ are hydrogen and R², R³, R⁵ and R⁶, independently,are hydrogen, fluoro, methyl or methoxy. It is preferred that n is zero,1, or 2 and more preferably n is 1. Preferably, tet is 1H-tetrazol-5-ylor 1-substituted-1H-tetrazol-5-yl. More preferably, tet is1-methyl-1H-tetrazol-5-yl, 1-ethyl1H-tetrazol-5-yl,1-methylethyl-1H-tetrazol-5-yl or1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl and most preferably, tet is1-methyl-1H-tetrazol-5-yl. It is preferred that X is --OH or ═O and mostpreferably X is --OH. Preferably, R⁸ is hydrogen, C₁₋₆ alkyl or apharmaceutically acceptable cation. Most preferably, R⁸ is apharmaceutically acceptable cation especially sodium or potassium.

In the compounds of Formula I wherein A contains two asymmetric carbonatoms bearing the hydroxy group, the erythro isomer is preferred and the(3R,5S) isomer being most preferred. In the compounds of Formula Iwherein A contains two asymmetric carbon atoms in the lactone form, thetrans isomer is preferred and the (4R,6S) isomer being most preferred.

The compounds of Formula I may be prepared by various procedures,preferably starting from a compound of the Formula IIa or IIb ##STR23##wherein R¹ and R⁴ each are independently hydrogen, halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy or trifluoromethyl; R², R³, R⁵ and R⁶ each are independentlyhydrogen, halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; and R⁷ is C₁₋₄ alkyl, C₁₋₄alkoxy(lower)alkyl, (2-methoxyethoxy)methyl or R^(7a) in which R^(7a) istriphenylmethyl.

The compounds of Formulae IIa and IIb may be prepared from theoptionally substituted benzophenones III by aldol condensation to thetetra substituted olefin IV and conversion to the tetrazole ester Vfollowed by alkylation of the tetrazole moiety and reduction of theester group in compounds VI and VII with subsequent oxidation of theresulting alcohols VIII and IX, as shown in Reaction Scheme 1. ##STR24##

In Reaction Scheme 1, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as previouslydefined. The optionally substituted benzophenones of the Formula III maybe prepared by the general and well-known Friedel Crafts reaction of asubstituted phenyl catalyzed by Lewis acids, e.g., with aluminumchloride in carbon tetrachloride at about 0° C. A large number ofsubstituted benzophenones are known and their prepartion are describedin the art while many others are commercially available. For example,many of the starting materials of Formula III are described by G. Olahin /Friedel-Crafts and Related Reactions, Vol. 3, Part 1 and 2,Interscience Publishers, New York, 1964 and references therein. TheFriedel Crafts reaction may produce a mixture of benzophenones and, ifso produced, the mixture may be separated by conventional techniquesknown in the art.

The appropriate benzophenone of the Formula III may be treated withethyl cyanoacetate in a solvent mixture containing glacial acetic acidand an organic solvent such as benzene or toluene in the presence of acatalyst preferably β-alanine. The reaction is allowed to proceed at thereflux temperature of the solvent and the water which is produced isazeotropically removed with a Dean-Stark trap or similar apparatus untilthe production of the tetra substituted olefin IV is essentiallycomplete. The nitrile group in compound IV is then converted to theheterocyclic tetrazole moiety of compound V by conducting the reactionwith azidotributylstannane neat or in an inert organic solvent such asbenzene, toluene or xylene at the reflux temperature of the solvent.

The 1H-tetrazole compound of Formula V may then be alkylated withvarious alkylating agents by methods well-known to those skilled in theart. Thus, the 1H-tetrazole of Formula V may be treated with a strongbase such as sodium hydride in a non-reactive solvent, e.g., benzene,toluene, diethyl ether and N,N-dimethyl-formamide or mixture thereof ata temperature from -30° C. to about 50° C. and then with an alkylatingagent, e.g., methyl iodide, ethyl iodide, bromotriphenylmethane, and thelike or with isobutylene in the presence of strong acid such as sulfuricacid. The temperature is not critical and will usually depend on thealkylating agent employed. This non-specific alkylation produces anisomeric mixture of alkylated products which may be separated byconventional procedures such as crystallization or chromatography togive the desired 1-substituted tetrazole compounds VI and 2-substitutedtetrazole compounds VII.

It should be appreciated by those skilled in the art that thecombination of reaction conditions with the specific alkylating agentemployed may produce predominately one isomer. For example, when thecompound of Formula V wherein R¹ and R⁴ are para-fluoro and R², R³, R⁵R⁶ are hydrogen, the alkylation of compound V with isobutylene producespredominately the 2-isomer tetrazole as is demonstrated in Example 32.Alternatively, the conditions of the alkylation reaction may be variedto produce the desired tetrazoles VI and VII in ratios varying fromabout 1:1 to about 5:1. When it is desired to prepare compounds ofFormula I wherein R⁷ is hydrogen, the alkylation of Compound V with aprotecting group such as triphenylmethyl is preferred. In this instance,the 2-isomer of compound VII is predominately produced as isdemonstrated in Example 106. Subsequent removal of the protecting groupwill then produce a compound of Formula I wherein R⁷ is hydrogen. Thus,it should be evident to one skilled in the art that the relative amountsof alkylated products VI and VII may be influenced by the reactionconditions and reagents employed.

The tetrazole esters of the Formulae VI and VII may then be convertedtogether as a mixture or, preferably, individually after separation bystandard techniques to the alcohols VIII and IX, respectively, by aseries of known reactions. According to one reaction route, the compoundof Formula VI is first hydrolyzed by conventional methods, such as basehydrolysis, i.e., lithium hydroxide, potassium hydroxide and sodiumhydroxide. The resulting acid (i.e. Example 5) is then converted to anacyl chloride (Example 6A) by reacting with a reagent such as oxalylchloride in methylene chloride at reflux temperature and the resultingacyl chloride is reduced with a reducing agent, preferably, lithiumaluminum hydride in tetrahydrofuran at -78° C. to produce the alcoholsof the Formula VIII. The alcohols of Formula IX may be prepared from theester of Formula VII by a similar series of reactions utilized toconvert the esters VI to the alcohols VIII. Alternatively, and morepreferably, the alcohols VIII and IX may be prepared in one step fromthe corresponding esters VI and VII by reduction with reducing agentssuch as diisobutylaluminum hydride in a non-reducible inert solvent suchas methylene chloride, at low temperatures, preferably at about -78° C.

The mixture of allylic alcohols of Formulae VIII and IX may be readilyoxidized by conventional oxidizing agents such as pyridiniumchlorochromate in a non-reactive solvent, preferably, methylene chlorideat ambient temperature. More preferably, the separated allylic alcoholsof Formula VIII and IX may individually be oxidized in the same mannerto produce the corresponding allylic aldehydes of Formula IIa and IIb.

The compounds of Formula I may be prepared from a compound of FormulaIIa or IIb by various alternative reaction schemes via several classesof novel intermediates. It should be understood by those skilled in theart that the prepartion of compounds of Formula I wherein n is 0, 1 or 2will necessarily involve three novel aldehyde intermediates. Thus, if itis desired to prepare compounds of Formula I wherein n=0, then thecompound of Formula IIa or IIb is subjected to the appropriate anionalkylation as described herein. However, if it is desired to preparecompounds of Formula I wherein n=1 or 2 then the appropriate Wittigreactions are carried out in order to prepare the necessary novelhomologous aldehydes X and XI for the 1-isomer and aldehydes XII andXIII for the 2-isomer, as shown in Reaction Schemes 2 and 3,respectively. ##STR25##

In Reaction Schemes 2 and 3, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ are aspreviously defined and R⁷ may also be R^(7a) in which R^(7a) istriphenylmethyl. For example, in Reaction Scheme 2, an allylic aldehydeof Formula IIa may be treated with triphenylphosphoranylideneacetaldehyde in a non-reactive solvent such as benzene, toluene,tetrahydrofuran, 1,2-dimethoxyethane and the like. The temperature ofthe reaction is not critical and can be conducted at from ambienttemperature to the reflux temperature of the solvent. For convenience weprefer to conduct the reaction at reflux temperature. It should beunderstood and appreciated by those skilled in the art that the reactionconditions and the number of equivalents of triphenylphosphoranylideneacetaldehyde utilized per equivalent of a compound of Formula IIa iscritical. If only one or slightly more than one equivalent of Wittigreagent is employed but the reaction conditions are not carefullycontrolled. e.g., time, temperature, mode of addition, etc., then theremay be produced a mixture of diene aldehyde X and triene aldehyde XI.The ratio of aldehydes X and XI will naturally depend on the reactionconditions employed. In a specific example described herein, Example 8,there is produced about a 9:1 ratio of an aldehyde of general Formulae Xand XI from the corresponding aldehyde of general Formula IIa. Thewittig reaction may also be used to assist in the selective reaction andseparation of compounds by utilizing less than one equivalent of theWittig reagent to produce mostly the diene aldehyde X. For example, theuse of half an equivalent of Wittig reagent as described in Example 69provided the desired diene aldehyde X and unreacted aldehyde IIa whichcould now be more readily separated. Preferably, the reaction isconducted with about one equivalent of Wittig reagent under controlledreaction conditions, for example, as described in Example 77 to producethe desired diene aldehyde X without any detectable amount (by NMR) ofthe homologous triene aldehyde. However, if it is desired to prepare thetriene aldehydes of Formula XI then the reaction of the aldehyde ofFormula IIa is carried out with at least two equivalents of the Wittigreagent or, alternatively, the diene aldehyde X is reacted with anadditional equivalent of the Wittig reagent to produce the trienealdehyde of Formula XI. Thus, it can be readily appreciated by thoseskilled in the art that the preparation of the desired homologatedaldehydes X and XI wherein n is 1 or 2, respectively can be controlledas desired by employing the appropriate amount of Wittig reagent andreaction conditions.

Conversion of an aldehyde of Formula IIb to the correspondinghomologated diene aldehyde of Formula XII and triene aldehyde of FormulaXIII, as shown in Reaction Scheme 3, may be prepared by proceduressimilar to those described above for the preparation of the aldehydes ofFormulae X and XI. It should be appreciated that some of the vinylogousaldehydes of Reaction Schemes 2 and 3 are readily and convenientlyisolated while others being more difficult. In specific cases where thealdehydes were difficult to separate by the chromatography systemsutilized herein, the mixture of aldehydes, for example, aldehydes X andXI are employed in the next step where the separation and isolation ofdiene and triene compounds may be more readily carried out bychromatography or other conventional techniques.

The compounds of Formula I wherein X is --OH may be prepared from acompound of the Formula IIa, IIb, X, XI, XII or XIII by the generalreaction route shown in Reaction Scheme 4. For the purposes ofdiscussion all the aldehydes of Reaction Schemes 2 and 3 are combined inone Formula and are designated as the compounds of Formula XIV wherein nis 0, 1 or 2 and R¹, R², R³, R⁴, R⁵, and R⁶ are as previously defined.##STR26##

In Reaction Scheme 4, the penultimate intermediate of Formula XV whereinR⁹ is a hydrolyzable ester group such as methyl, ethyl and t-butyl estermay be prepared from the corresponding aldehyde of Formula XIV byreaction with the dianion of acetoacetate ester generated in situ, forexample, as described in Examples 10 and 90. The reaction may beconducted in an inert organic solvent such as tetrahydrofuran at lowtemperatures from -78° C. to about 0° C. and preferably from about -78°C. to -40° C. until the reaction is essentially complete. If a compoundof the Formula XV were prepared from a mixture of aldehydes of FormulaXIV, then separation of the compounds of Formula XV especially wherein nis 1 and 2 may be advantageously separated and isolated at this stage byconventional techniques.

The ketone ester of Formula XV may be reduced to the dihydroxy ester ofFormula Ia by reduction of the ketone radical with reducing agentswell-known in the art, e.g., sodium borohydride, sodiumcyanoborohydride, zinc borohydride, disiamylborane, diborane, ammoniaborane, t-butylamine borane, pyridine borane, lithiumtri-s-butylborohydride or other similar reducing agents which will notreduce nor reduce nor hydrolyze the carboxylic ester radical.Preferably, the reduction is carried out in a stereospecific manner by atwo-step stereospecific reduction in order to maximize the production ofthe preferred erythro isomer of the compound of Formula I. Thestereospecific reduction of a compound of Formula XV is carried out withtrisubstitutedalkylboranes, preferably triethylborane, oralkoxydialkylboranes, preferably methoxydiethylborane orethoxydiethylborane [Tetrahedron Letters, 28, 155 (1987)] at atemperature of about -70° C. to about ambient temperature. The complexwhich is produced is then reduced with sodium borohydride at atemperature of about -50° C. to about -78° C. in an inert organicsolvent such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane,preferably, tetrahydrofuran. The reduction is then completed by theaddition of methanol. The resulting compound of Formula Ia produced fromthe stereospecific reduction contains two asymmetric carbon atomsbearing the hydroxy group in an erythro configuration. Thus, reductionof the ketone radical under the conditions employed herein producesmostly the erythro isomers of the compounds of Formula Ia and only asmall amount of the less preferred threo isomers. The ratio oferythro-threo isomers produced will vary according to the specificcompound utilized and the reaction conditions employed. Normally, thisratio will be approximately 9:1 to 9.8:0.2. However, the use of anon-specific reduction will normally produce a 1:1 mixture of isomers.Nevertheless, the mixture of isomers may be separated and purified byconventional techniques and then converted to the compounds of generalFormula I in a conventional manner well-known to those skilled in theart.

The compounds of Formula I in which A is defined by X is --OH and R⁸ ishydrogen (Ic), a hydrolyzable ester group (Ia) or a cation to form anon-toxic pharmaceutically acceptable salt (Ib) and in which A is in theform of a lactone (Id) may be prepared and, if desired, interconvertedas shown in Reaction Scheme 5. ##STR27##

In Reaction Scheme 5, R¹, R², R³, R⁴, R⁵, R⁶, tet and n are aspreviously defined, R⁹ is a hydrolyzable ester group and M.sup.⊕ is acation. The preparation of a compound of Formula Ib from a compound ofFormula Ia is preferably carried out by base hydrolysis with bases suchas sodium hydroxide, potassium hydroxide and lithium hydroxide in anorganic solvent such as tetrahydrofuran, ethanol and methanol at atemperature from 0° C. to about 50° C. The form of the cation isnormally determined by the corresponding cation of the hydroxideemployed. However, if desired, the cation may be exchanged for anothercation by treatment with ion-exchange resins.

The compound of Formula Ic may be cyclized to the corresponding lactoneof Formula Id by conventional lactonization methods, for example, byheating the acid in an inert organic solvent such as benzene, tolueneand xylene and azetropically removing the water which is produced or bytreating the compound of Formula Ic in an inert organic solvent, e.g.,toluene, benzene, diethyl ether or methylene chloride with an acid suchas p-toluenesulfonic acid, in the presence of a drying agent, e.g.,NaSO₄, MgSO₄ or molecular sieves. Preferably, the lactonization iscarried out by activation of the carboxyl radical with a carbodiimidesuch as described in the Examples in an inert organic solvent such astetrahydrofuran, and preferably, in methylene chloride or ethyl acetateat about ambient temperature to produce the lactone of Formula Id. Ifthe relative stereochemical configuration of the two carbon atomsbearing the hydroxy groups are established as erythro in Formula Ic,then the lactonization will produce the preferred trans lactone ofFormula Id, otherwise the lactonization will produce a mixture of transand cis lactones.

The resulting lactone of Formula Id may, if desired, be hydrolyzed withbase or acid to produce the compounds of Formula Ib or Formula Ic,respectively, or the lactone may be hydrolyzed in the presence of analcohol to produce the compounds of Formula Ia.

The compounds of Formula I wherein X is ═0 in the definition of thesubstituent A may be produced by reaction of an appropriate aldehyde ofFormula XIV with the phosphonate compound of Formula XVI as shown inReaction Scheme 6. ##STR28##

In Reaction Scheme 6, R¹, R², R³, R⁴, R⁵, R⁶, tet and n are aspreviously defined, and R⁹ is a hydrolyzable ester group. Thepreparation of a compound of Formula Ie may be carried out asillustrated in Reaction Scheme 6 in an inert organic solvent such asacetonitrile, methylene chloride, chloroform, tetrahydrofuran and thelike at a temperature of from 0° C. to the reflux temperature of thesolvent and preferably at ambient temperature in the presence of asuitable organic base. Suitable organic bases include tertiary aminessuch as triethylamine, N-methylmorpholine, N-methylpiperidine,1,4-diazabicyclo[2.2.2]octane ("DABCO"),1,8-diazabicyclo[5.4.0]undec-7-ene("DBU"), 1,5-diazabicyclo[4.3.0]non-5-en("DBN") and the like. The resulting compound of FormulaIe wherein R⁹ is a hydrolyzable ester group may, if desired, behydrolyzed by conventional methods to produce compounds of the Formula Iwherein R⁹ is converted to the R⁸ substituent as described herein andillustrated in Reaction Scheme 5.

In an alternate reaction route, a preferred embodiment of the compoundsof Formula I wherein n is 1, X is --OH and tet is1-methyl-1H-tetrazole-5-yl, may be prepared by the procedure describedin Reaction Scheme 7. ##STR29##

In Reaction Scheme 7, R¹, R², R³, R⁴, R⁵, and R⁶ are as previouslydefined, R⁹ is a hydrolyzable ester group, R¹⁰ is t-butyldiphenylsilyland Z is ##STR30## in which R¹² is C₁₋₄ alkyl, R¹³ is phenyl which isunsubstituted or substituted by one or two C₁₋₄ alkyl or chlorosubstituents and X is bromo, chloro or iodo. The phosphonium salt ofFormula XVII or phosphonate of Formula XVIIa which is described herein,in U.S. patent application Ser. No. 018,558, filed Feb. 25, 1987, and inthe continuation-in-part U.S. patent application Ser. No. 151512 filedFeb. 18, 1988 (concurrently) by us and our colleagues NeelakantanBalasubramanian and Peter J. Brown may be reacted with the silylprotected aldehyde of Formula XVIII which is itself prepared by theprocedures described in Tetrahedron Letters, 25, 2435 (1984) and also inU.S. Pat. No. 4,571,428 to produce the silyl protected compound ofFormula XIX. The reaction may be carried out in an inert organic solventsuch as tetrahydrofuran and N,N-dimethylformamide in the presence of astrong base, for example, lithium diisopropylamide, n-butyllithium orpotassium t-butoxide at a temperature of about -78° C. to about 0° C.The compound of Formula XIX may then be readily desilylated bywell-known procedures such as 48% hydrofluoric acid and preferably, withtetrabutylammonium fluoride in an inert organic solvent such astetrahydrofuran and acetonitrile to produce the erythro compounds ofFormula If, a more preferred embodiment of the compounds of Formula Ia.The R⁹ substituent may then be converted to the R⁸ substituent asdescribed herein and illustrated in Reaction Scheme 5.

When it is desired to prepare mostly one stereoisomer of a compound ofFormula I, it is preferred to employ optically pure starting materials.The various procedures which may be used to prepare one isomer of acompound of Formula I wherein X is --OH are illustrated in ReactionSchemes 8, 9 and 10. The most preferred isomer of a compound of FormulaI wherein A is defined as ##STR31## is the (3R, 5S) isomer, and the mostpreferred isomer of a compound of Formula I where A is defined as##STR32## is the (4R,6S) isomer. It should be appreciated that it isnecessary to have only one of the above definitions of A for compoundsof Formula I since they may be interconverted as shown in ReactionScheme 5. To illustrate the use of optically pure starting materials,the preparation of a preferred embodiment of compounds of Formula I suchas the (3R,5S) isomer of compounds of Formula If by three syntheticroutes are shown in Reaction Schemes 8, 9 and 10. ##STR33##

In Reaction Scheme 8, R¹, R², R³, R⁴, R⁵, R⁶ are as previously definedand R¹⁰ is t-butyldiphenyl-silyl. The starting materials XX and XXII areknown and their preparation are described in Tetrahedron Letters, 23,4305 (1982) and U.S. Pat. No. 4,613,610, respectively. The compound ofFormula XVII or Formula XVIIa may be reacted with the compound ofFormula XX in an inert organic solvent to produce the compounds ofFormula XXI which then may be hydrolyzed with acid in a solvent mixturecontaining acetic acid, tetrahydrofuran and water followed by mildoxidation with pyridinium chlorochromate in methylene chloride toproduce the desired trans-lactone of Formula XXIII. Alternatively, thetrans-lactone of Formula XXIII may be produced directly by thecondensation of a compound of Formula XVII and a compound of FormulaXXII. Desilylation with 48% hydrofluoric acid in acetonitrile andpreferably with tetrabutylammonium fluoride will produce the (4R,6S)enantiomer of a compound of Formula Ig which can then, if desired, beconverted to the (3R,5S) enantiomer of a compound of Formula If.##STR34##

The second stereospecific route is shown in Reaction Scheme 9 whereinR¹, R², R³, R⁴, R⁵, and R⁶ are as previously defined, R⁹ is ahydrolyzable ester group and R¹⁰ is t-butyldimethylsilyl. The dienealdehyde of Formula Xa may be treated with sodium cyanide and thecyanohydrin thereby produced is converted to the tetrahydropyranyl (THP)derivative of Formula XXIV. The compound of Formula XXVI may be preparedby reacting the compound of Formula XXIV which is first treated with astrong base such as n-butyllithium with the iodo ester of Formula XXV.Preparation of the optically pure protected iodohydrin XXV wherein R¹⁰is t-butyldimethylsilyl and R⁹ is methyl is described in TetrahedronLetters, 25, 2951 (1985). Removal of the protecting groups may becarried out by acid hydrolysis to produce the keto-alcohol of FormulaXXVII. The stereospecific reduction of a compound of Formula XXVIIemploying sodium borohydridetriethylborane or sodiumborohydride-alkoxydialklborane as described herein may be used to reducethe 5-keto group to the desired (5S) stereochemistry to produce the(3R,5S) enantiomer of the compound of Formula If. Thus, Reaction Scheme9 provides a method for the preparation of the (3R,5S) isomer of acompound of Formula I by utilizing the optically pure starting materialXXV which provides the appropriately substituted carbon atom in the3-position to direct the stereospecific reduction of the 5-ketofunction. ##STR35##

The third stereospecific route is shown in Reaction Scheme 10 whereinR¹, R², R³, R⁵, R⁶ and R⁹ are as previously defined. The startingmaterial of Formula XXVIII is known and its preparation is described inTetrahedron Letters, 25, 5031 (1984). The compound of the Formula XXVIIIis first treated with a non-nucleophilic base, preferably lithiumdiisopropylamide in an inert solvent such as tetrahydrofuran and theenolate which is produced is then reacted with an allylic aldehyde ofthe Formula Xa to produce the triphenyl ester of Formula XXIX. When thecompound of Formula XXIX is treated with sodium methoxide in methanolthe methyl ester of Formula XXX may be isolated. When the methyl esterof Formula XXX is reacted with the anion of tert-butyl acetate which isgenerated in situ with a non-nucleophilic base such as lithiumdiisopropylamide there is thereby produced the keto ester of FormulaXXXI. Alternatively, the preparation of a compound of Formula XXXI maybe carried out by directly treating the triphenyl ester of Formula XXIXwith the anion of t-butyl ester. Selective stereospecific reduction ofthe resulting keto functionality of Formula XXXI with sodiumborohydride-triethylborane or sodium borohydridealkoxydialkylborane asdescribed herein may be used to produce the (3R,5S) enantiomer of acompound of Formula If. Accordingly, Reaction Scheme 10 provides amethod for the preparation of the (3R,5S) isomers of a compound ofFormula I by employing the optically pure starting material XXVIII whichprovides the appropriately substituted carbon atom in the 5-position todirect the stereospecific reduction of the 3-keto function. In aspecific example described herein wherein R¹ and R⁴ are fluoro and R²,R³, R⁵ and R⁶ are hydrogen there is provided a method for thepreparation of a compound of Formula If which is mostly the (3R,5S)enantiomer.

In a preferred embodiment of the invention the compounds of Formula Ihave the structure ##STR36## wherein R¹ and R⁴ each are independentlyhydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl;

R²,R³,R⁵ and R⁶ each are independently hydrogen, halogen, C₁₋₄ alkyl orC₁₋₄ alkoxy;

n is an integer of from 0 to 2 inclusive;

A is ##STR37## R⁷ is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy(lower)alkyl or(2-methoxyethoxy)methyl;

X is --OH or ═O; and

R⁸ is hydrogen, a hydrolyzable ester group or a cation to form anon-toxic pharmaceutically acceptable salt.

In a more preferred embodiment of the invention the compounds of FormulaI have the structure ##STR38## wherein R¹, R², R³, R⁴, R⁵ and R⁶ eachare independently hydrogen, fluoro, chloro, methyl or methoxy; R⁷ isC₁₋₄ alkyl; and R⁸ is hydrogen, C₁₋₆ alkyl or a cation to form anon-toxic pharmaceutically acceptable salt. In a particularly preferredembodiment, R⁷ is methyl.

In another more preferred embodiment of the invention the compounds ofFormula I have the structure ##STR39## wherein R¹, R², R³, R⁴, R⁵ and R⁶each are independently hydrogen, fluoro, chloro, methyl or methoxy; andR⁷ is C₁₋₄ alkyl. In a particularly preferred embodiment, R⁷ is methyl.

As presently envisaged, the particularly preferred compounds of theinvention are

(a) ethyl9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate,

(b)9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(c) sodium9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate,

(d) (3R,5S) enantiomer of9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(e) (3R,5S) enantiomer of sodium9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate,

(f)trans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(g) (4R,6S) enantiomer oftrans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(h)11,11-bis(4-fluorophenyl)-3,5-dihydroxy-10-(1-methyl-1H-tetrazol-5-yl)-6,8,10-undecatrienoicacid or a non-toxic pharmaceutically acceptable salt,

(i) sodium11,11-bis(4-fluorophenyl)-3,5-dihydroxy-10-(1-methyl-1H-tetrazol-5-yl)-6,8,10-undecatrienoate,

(j)trans-6-[4,4-bis(4-fluorophenyl)-3-(2-methyl-2H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(k)9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-methyl-2H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(l) sodium9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-methyl-2H-tetrazol-5-yl)-6,8-nonadienoate,

(m)9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-5-oxo-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(n) sodium9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-5-oxo-6,8-nonadienoate,

(o)9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(p) sodium9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-6,8-nonadienoate,

(q) ethyl9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-6,8-nonadienoate,

(r)9,9-bis(4-fluoro-3-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(s) sodium9,9-bis(4-fluoro-3-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate,

(t)9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-ethyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(u) sodium9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-ethyl-1H-tetrazol-5-yl)-6,8-nonadienoate.

(v)9,9-bis(2,4-dimethylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(w) sodium9,9-bis(2,4-dimethylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate,

(x)9,9-bis-(4-fluorophenyl)-3,5-dihydroxy-8-[1-(2-methoxyethoxy)-methyl-1H-tetrazol-5-yl]-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(y) sodium9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-6,8-nonadienoate,

(z)9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(aa) sodium9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate,

(bb)9,9-bis(2-fluoro-4-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt,

(cc) sodium9,9-bis(2-fluoro-4-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate.

In another aspect, this invention provides novel intermediates of theformula ##STR40## wherein R¹ and R⁴ each are independently hydrogen,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, or trifluoromethyl; R², R³, R⁵ and R⁶each are independently hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; tetis ##STR41## n is an integer of from 0 to 2, inclusive; and R⁷ is C₁₋₄alkyl, C₁₋₄ alkoxy(lower)alkyl, (2-methoxyethoxy)methyl or R^(7a) inwhich R^(7a) is triphenylmethyl.

In a preferred embodiment, the compounds of Formula XIV have thestructure ##STR42## wherein R¹ and R⁴ each are independently hydrogen,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl; R², R³, R⁵ and R⁶each are independently hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; nis an integer of from 0 to 2, inclusive; and R⁷ is C₁₋₄ alkyl, C₁₋₄alkoxy(lower)alkyl or (2-methoxyethoxy)methyl.

In a more preferred embodiment, the compounds of Formula XIV have thestructure ##STR43## wherein R¹, R², R³, R⁴, R⁵ and R⁶ each areindependently hydrogen, fluoro, chloro, methyl or methoxy; and R⁷ isC₁₋₄ alkyl. In a particularly preferred embodiment, R⁷ is methyl.

In another more preferred embodiment, the compounds of Formula XIV havethe structure ##STR44## R¹, R², R³, R⁴, R⁵ and R⁶ each are independentlyhydrogen, fluoro, chloro, methyl or methoxy; and R⁷ is C₁₋₄ alkyl. In aparticularly preferred embodiment, R⁷ is methyl.

In still another aspect, this invention provides novel intermediates ofthe formula ##STR45## wherein R¹ and R⁴ each are independently hydrogen,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, or trifluoromethyl; R², R³, R⁵ and R⁶each are independently hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; nis an integer of from 0 to 2, inclusive; tet is ##STR46## R⁷ is C₁₋₄alkyl, C₁₋₄ alkoxy(lower)alkyl, (2-methoxyethoxy)methyl or R^(7a) inwhich R^(7a) is triphenylmethyl; and R⁹ is a hydrolyzable ester group.

In a preferred embodiment, the compounds of Formula XV have thestructure ##STR47## wherein R¹ and R⁴ each are independently hydrogen,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl; R², R³, R⁵ and R⁶each are independently hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; nis an integer of from 0 to 2, inclusive; R⁷ is C₁₋₄ alkyl, C₁₋₄alkoxy(lower)alkyl or (2-methoxyethoxy)methyl; and R⁹ is a hydrolyzableester group.

In a more preferred embodiment, the compounds of Formula XV have thestructure ##STR48## where R¹, R², R³, R⁴, R⁵ and R⁶ each areindependently hydrogen, fluoro, chloro, methyl or methoxy; and R⁷ isC₁₋₄ alkyl. In a particularly preferred embodiment, R⁷ is methyl.

The compounds of Formula I are competitive inhibitors of the enzyme3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the ratelimiting enzyme in cholesterol biosynthesis, and therefore, areselective suppressors of cholesterol biosynthesis in animals, includingman. Consequently, they are useful in the treatment ofhypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Thebiological activity of the compounds of Formula I may be demonstrated inthe following three different biological tests.

Test A: In Vitro Inhibition of Microsomal HMG-CoA Reductase:

The intact, fully activated microsomal form of rat liver HMG-CoAreductase (subunit MW ca 100,000 daltons) was prepared as described byParker, et al., Biochem. Biophys. Res. Commun., 125, 629-635 (1984), andused as the source of enzyme for assays. HMG-CoA reductase activity wasdetermined essentially by the method of Shapiro, et al., Biochem.Biophys. Acta., 370, 369-377 (1974), with modifications as described byIngebritsen and Gibson, Meth. Enzymol. 71, 486-497 (1981) with theexception that the internal standard ³ H-mevalonolactone is added aftertermination of the assay. In this procedure, the enzyme is assayed bymeasuring the formation of product, ¹⁴ C-mevalonate, from the substrate,[3-¹⁴ C]-HMG-CoA, in the presence of NADPH. The ¹⁴ C-mevalonate isconverted to its lactone and isolated by silica thin-layerchromatography (Whatman LK5D, developed in 50:50 benzene:acetone) in thepresence of ³ H-mevalonolactone as an internal standard. Assays wereconducted under conditions in which product formation was linear withrespect to time and enzyme concentration.

To measure reductase inhibition, test compounds dissolved in water ordimethylsulfoxide and diluted in buffer A (50 mM imidazole-HCl, 250 mMNaCl, 1 mM EDTA, 1 mM EGTA, 5 mM DTT, 20 μM leupeptin, pH=7.2) wereincubated with aliquots of microsomes (80-160 μg protein in buffer A)followed by addition of d,1-[3-¹⁴ C]-HMG-CoA (0.33 mM, 2.0 dpm/picomole)and NADPH (3.0 mM). The 50 percent inhibitory concentration (IC₅₀) foreach compound in Table 1 was calculated from the linear regression lineof the percent decrease (from control) in enzyme activity vs. logconcentration of inhibitor, determined using at least 4 dilutions ofeach test compound assayed in duplicate.

                  TABLE 1                                                         ______________________________________                                        Inhibition of Microsomal HMG-CoA Reductase                                    Compound of    IC.sub.50                                                      Example No.    μmolar                                                      ______________________________________                                        11             >330                                                           12             0.037 ± 0.01                                                13             1.09 ± 0.29                                                 15             5.7                                                            44             0.16                                                           65             1.6                                                            92             0.029                                                          99             0.58                                                           120            0.044                                                          126            0.19                                                           132            1.4                                                            ______________________________________                                    

Test B: Isolated Hepatocyte Cholesterol Biosynthesis Assay:

Intact parenchymal hepatocytes were isolated from male Wistar rats(180-280 g) fed cholestyramine-containing or normal diet, using thecollagenase perfusion method essentially as described by Seglen, inMethods in Cell Biology (D. Prescott, ed.) Vol. 13, pp. 29-83, AcademicPress, New York (1976). Cell preparations were used only when viability(trypan blue exclusion) exceeded 90%. Cholesterol biosynthesis wasdetermined as the incorporation by hepatocytes of ³ H from [³ H]-waterinto total (cellular plus medium) 3β-hydroxy sterols as per Ingebritsen,et al., J. Biol. Chem., 254, 9986-9989 (1979). Hepatocyte sterols andlipids were isolated by a modification of the methods described byKates, in Techniques in Lipidology, (M. Kates, ed.), pp. 349, 360-363,North Holland Publ. Co., Amsterdam, 1972. To isolate sterols, cells areextracted with methanol:chloroform:water (2:1:0.8), the chloroform phaseis separated and extracted with benzene to remove traces of water, thendried under nitrogen. The residue is saponified at 75° C. with 0.30 NNaOH in methanol:water (9:1). The alkaline mixture is then extractedthree times with petroleum ether to yield the non-saponifiable lipidswhich include the free as well as initially esterified cholesterol. Theextract is dried under nitrogen in the presence of carrier cholesterol(0.1 mg) and 10% benzene, and the residue is dissolved inacetone:ethanol (1:1). Finally, the 3β-hydroxysterols are precipitatedwith an excess of digitonin, the precipitate is washed in acetone, driedunder nitrogen, and dissolved in toluene:methanol (1:1). The ³H-labelled sterols are quantified by liquid scintillation and correctedfor counting efficiency. In some tests ¹⁴ C-cholesterol was added toinitial extractions as an index of recovery, which averaged 80±3%.

To measure inhibition of cholesterol synthesis, duplicate or triplicatealiquots of freshly isolated cells were suspended (100 mg cell netweight in 2.0 mL) in Eagle's Minimal Essential Medium containingbicarbonate and HEPES buffer, pH 7.35, plus 2% bovine serum albuminunder a 95% 0₂ +5% CO₂ atmosphere. Cells were preincubated for 10minutes with or without aliquots of test compounds added as watersolutions of sodium salts or as dimethylsulfoxide solutions of lactones.Controls received vehicle alone. [³ H]-water (1.0 mCi per mL incubationvolume) or 2-¹⁴ C-acetate (0.5 μCi per mL incubation volume) was thenadded to each and the cells were incubated with constant shaking for 60minutes at 37°. These conditions produced time-linear incorporation oftritium or ¹⁴ C into sterols. The IC₅₀ for inhibition of sterolsynthesis by test compounds which is shown in Table 2 was calculatedfrom the linear regression curve of % inhibition (compared to controls)vs. log concentration using at least 4 concentrations of inhibitor. TestB therefore measures the ability of test substances to inhibit theintracellular synthesis of cholesterol.

                  TABLE 2                                                         ______________________________________                                        Inhibition of Isolated                                                        Hepatocyte Cholesterol Biosynthesis                                           Compound of       IC.sub.50                                                   Example No.       nmolar                                                      ______________________________________                                        12                23.0 ± 11                                                13                24.0                                                        138                7.4                                                        Mevinolin (Lovastatin)                                                                          46.0 ± 26                                                ______________________________________                                    

Test C: In Vivo Acute Cholesterol Biosynthesis Inhibition in Rats:

Male Wistar rats (160-200 g, housed 2 per cage) were maintained onnormal diet (Purina Rat Chow and water, ad libitum) for at least 7 dayson a reversed lighting schedule (7:00 a.m. to 5:00 p.m. dark). Food wasremoved 15 hours prior to dosing. Compounds were administered at 8:00a.m. by intragastric intubation using 0.5-1.0 mL of water or propyleneglycol solutions of sodium salts, lactones, or esters of the testcompounds. Controls received equal volumes of the vehicle.

Thirty minutes after receiving the test substances, rats were injectedintraperitoneally with 0.9 mL of 0.9% NaCl containing approximately 120μCi per kg body weight of sodium [1-¹⁴ C] acetate (1-3 mCi/mmol). Aftera 60 minute incorporation period, rats were sacrificed and liver andblood samples were obtained. Aliquots of plasma (1.0 mL) obtained bycentrifugation of heparin+EDTA-treated blood, and aliquots of liverhomogenates (equivalent to 0.50 g liver wet weight) were taken fordetermination of radiolabeled 3β-hydroxy sterols. Sterol isolation forthe liver samples followed the method of Kates as described above forthe hepatocyte procedure (Test B) while the plasma samples were directlysaponified followed by isolation of the digitonin-precipitable sterols.¹⁴ C-labelled sterols were quantified by liquid scintillation counting(efficiency corrected). Mean percent inhibition of ¹⁴ C incorporatedinto liver and into plasma cholesterol were calculated for groups oftreated animals and compared to mean values for controls conductedsimultaneously.

Therefore, Test C provides information on the ability of test substancesto suppress the de novo biosynthesis of cholesterol in vivo in rats withoral dosing. For example, using Test C, the compound of Example 12yielded a 50% Inhibitory Dose (ED₅₀) of 0.08 mg/kg for both plasma andliver cholesterol, and for the reference agent mevinolin, an ED₅₀ valueof 0.04 mg/kg was obtained which was comparable to values obtained formevinolin using a similar procedure [Alberts, et al., Proc. Natl. Acad.Sci., 77, 3957-3961 (1980)].

The results of the above in vitro and in vivo Tests A, B and Cdemonstrate that the compounds of Formula I inhibit cholesterolbiosynthesis and, therefore, are useful in the treatment ofhypercholesterolemia.

In another embodiment, this invention includes pharmaceuticalcompositions comprising at least one compound of Formula I incombination with a pharmaceutical carrier or diluent.

In another embodiment, this invention relates to a method of inhibitingcholesterol biosynthesis in an animal in need thereof, which comprisesadministering to said animal an effective cholesterol inhibitory dose ofat least one compound of Formula I.

For therapeutic use, the pharmacologically active compounds of Formula Iwill normally be administered as a pharmaceutical composition comprisingas the (or an) essential active ingredient at least one such compound inassociation with a solid or liquid pharmaceutically acceptable carrierand, optionally, with pharmaceutically acceptable adjuvants andexcipients employing standard and conventional techniques.

The pharmaceutical compositions may be administered orally, parenterallyor by rectal suppository. A wide variety of pharmaceutical forms may beemployed. Thus, if a solid carrier is used, the preparation may betableted, placed in a hard gelatin capsule in powder or pellet form, orin the form of a troche or lozenge. The solid carrier may containconventional excipients such as binding agents, fillers, tabletinglubricants, disintegrants, wetting agents and the like. The tablet may,if desired, be film coated by conventional techniques. If a liquidcarrier is employed, the preparation may be in the form of a syrup,emulsion, soft gelatin capsule, sterile vehicle for injection, anaqueous or non-aqueous liquid suspension, or may be a dry product forreconstitution with water or other suitable vehicle before use. Liquidpreparations may contain conventional additives such as suspendingagents, emulsifying agents, non-aqueous vehicle (including edible oils),preservatives, as well as flavoring and/or coloring agents. Forparenteral administration, a vehicle normally will comprise sterilewater, at least in large part, although saline solutions, glucosesolutions and like may be utilized. Injectable suspensions also may beused, in which case conventional suspending agents may be employed.Conventional preservatives, buffering agents and the like also may beadded to the parenteral dosage forms. The pharmaceutical compositionsare prepared by conventional techniques appropriate to the desiredpreparation containing appropriate amounts of the active component, thatis, the compound of Formula I according to the invention.

The dosage of the compounds of Formula I will depend not only on suchfactors as the weight of the patient and mode of administration, butalso on the degree of cholesterol biosynthesis inhibition desired andthe potency of the particular compound being utilized. The decision asto the particular dosage to be employed (and the number of times to beadministered per day) is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention for the satisfactory inhibition or reduction ofcholesterol biosynthesis, each oral dosage unit will contain the activeingredient in an amount of from about 0.01 mg/kg to about 10 mg/kg bodyweight, and most preferably from about 0.05 mg/kg to about 2 mg/kg bodyweight. The active ingredient will preferably be administered in equaldoses from one to four times a day. However, usually a small dosage isadministered, and the dosage is gradually increased until the optimaldosage for the host under treatment is determined.

A particularly preferred method for the preparation of the morepreferred embodiment of the present invention having the formula##STR49## wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined;is described in U.S. patent application Ser. No. 018,558, filed February25, 1987 and in the corresponding continuation-in-part U.S. patentapplication Ser. No. 151,512, filed Feb. 18, 1988 (concurrently) by usand our collegues Neelakantan Balasubramanian and Peter J. Brown.

The compounds of Formula IIc may be prepared by various procedures, andpreferably from a compound of the formula ##STR50## wherein R¹, R², R³,R⁴, R⁵ and R⁶ are as previously defined; and R¹¹ is hydrogen, C₁₋₆alkoxycarbonyl or methyl.

The use of the compounds of Formula XXXII provides an efficient andselective process which avoids the alkylation mixtures described inReaction Scheme 1.

The compounds of Formula XXXII may be prepared from the optionallysubstituted benzophenones of Formula III by alkylation with theappropriately 5-substituted 1-methyltetrzaole of Formula XXXIII followedby dehydration of the resulting tertiary alcohol of Formula XXXIV, asshown in Reaction Scheme 11. ##STR51##

In Reaction Scheme 11, R¹, R², R³, R⁴, R⁵, R⁶ and R¹¹ are as previouslydefined. The optionally substituted benzophenones of the Formula III maybe prepared by the general and well-known Friedel Crafts reaction. Thestarting material of Formula XXXIII wherein R¹¹ is hydrogen iscommercially available while the starting materials wherein R¹¹ is C₁₋₆alkoxycarbonyl or methyl may be prepared by reacting1,5-dimethyltetrazole with a strong base such as butyllithium at atemperature of about -70° C. to about 0° C. and the resulting anionthereof is added to or treated with, preferably, ethyl chloroformate ormethyl iodide, respectively, as described herein.

The appropriate 5-substituted 1-methyltetrazole of Formula XXXIII may betreated with a strong base such as n-butyllithium at low temperatures offrom about -20° C. to about -78° C., and preferably, from about -40° C.to -78° C. in an inert organic solvent, e.g., tetrahydrofuran, diethylether, 1,2-dimethoxyethane and the like. The resulting anion of FormulaXXXIII may then be treated with the desired benzophenone of Formula IIIto produce the corresponding tertiary alcohols of Formula XXXIV.

The compounds of Formula XXXII may be prepared from the compounds ofFormula XXXIV by conventional dehydration procedures. The dehydrationmay be carried out by heating the alcohol of Formula XXXIV in a suitableinert organic solvent, e.g., toluene, benzene or xylene with a smallamount of organic or mineral acid such as p-toluenesulfonic acid orsulfuric acid in the presence of a drying agent, e.g., Na₂ SO₄, MgSO₄,molecular sieves, etc., or preferably, the water which is produced isazeotropically removed with a Dean-Stark trap or similar apparatus.Alternatively, the alcohol of Formula XXXIV may simply be heated withpotassium hydrogen sulfate at temperatures of about 190° C.

In the specific example wherein R¹¹ is ethoxycarbonyl, the reaction ofethyl 1-methyl-5-tetrazolylacetate with a benzophenone of Formula IIImay be conducted in the presence of titanium tetrachloride and carbontetrachloride to directly produce, in one step, the corresponding olefinof Formula XXXII.

The preferred aldehydes of Formula IIc may be prepared by variousprocedures from the compounds of Formula XXXII depending on which R¹¹substituent is employed in the procedure. Thus, it should be appreciatedby those skilled in the art, that the compounds of Formula XXXII whereinR¹¹ is ethoxycarbonyl (XXXIIa), hydrogen (XXXIIc) or methyl (XXXIId) maybe converted to the aldehydes of Formula IIc, as shown in ReactionScheme 12. ##STR52##

In Reaction Scheme 12, R¹, R², R³, R⁴, R⁵ and R⁶ are as previouslydefined. The alcohols of Formula XXXIIb may preferably be prepared inone step by reduction of the tetrazole ester of Formula XXXIIa withreducing agents such as diisobutylaluminum hydride in a non-reducibleinert solvent such as methylene chloride and tetrahydrofuran, at lowtemperatures, and preferably at about -78° C. The resulting allylicalcohols of Formula XXXIIb may then be readily oxidized by conventionaloxidizing agents such as pyridinium chlorochromate in a non-reactivesolvent, preferably, methylene chloride at ambient temperature toproduce the desired aldehyde of Formula IIc. The compounds of FormulaXXXIIc may be converted directly to the aldehydes of Formula IIc bytreating the anion of Formula XXXIIc, which is produced in situ in aninert organic solvent, e.g., tetrahydrofuran or 1,2-dimethoxyethane witha strong base such as n-butyllithium with ethyl formate.

The compounds of Formula IIc may also be prepared from the compounds ofFormula XXXIId by first treating the compounds of Formula XXXIId withN-bromosuccinimide in the presence of a catalyst such as azobisisobutyronitrile or benzoyl peroxide in carbon tetrachloride, and thenreacting the resulting allylic bromide of Formula XXXIIe with2-nitropropane by the general procedure described herein and in Org.Syn. Coll. Vol. IV, 932. Alternatively, the allylic bromide of FormulaXXXIIe may be prepared from the alcohol of Formula XXXIIb by treatmentwith carbon tetrabromide and triphenylphosphine.

In an alternate and preferred procedure for the preparation of compoundsof the Formula If there is provided intermediates of the Formulae XVIIand XVIIa, as shown in Reaction Scheme 13. ##STR53##

In Reaction Scheme 13, R¹, R², R³, R⁴, R⁶, R¹², R¹³ and X are aspreviously defined. The allylic bromide of Formula XXXIIe may be reactedin a conventional manner with phosphines such as triphenylphosphine inan inert organic solvent such as cyclohexane to produce the phosphoniumsalt of Formula XVII. Alternatively, the allylic bromide of FormulaXXXIIe may be reacted in a conventional manner with phosphites such astrimethyl phosphite and triethyl phosphite either neat or in an inertorganic solvent, and preferably, neat to produce the phosphonates ofFormula XVIIa.

The intermediates of Formulae XVII or XVIIa may then be converted to thecompounds of Formula If by a series of reactions shown in ReactionScheme 7.

Another particularly preferred method for the preparation of compoundsof the Formula If and Ig of the present invention is the use ofintermediates having the formulae ##STR54## in substantially the cisform wherein R¹⁶ and R¹⁷ each are C₁₋₄ alkyl or R¹⁶ and R¹⁷, takentogether with the carbon atom to which they are attached, iscyclopentyl, cyclohexyl or cycloheptyl and R¹⁹ is hydrogen, C₁₋₄ alkylor a metal cation. The preparation and use of the compounds of FormulaeXXXVa and XXXVb is described in U.S. patent application Ser. No.156,865, filed Feb. 18, 1989 (concurrently) by William T. Han and JohnJ. Wright.

The substituted 1,3-dioxane compounds of Formula XXXVa, XXXVb and othersimilar compounds described herein also contain two asymmetric carbonatoms at the 4 and 6 position as shown below, ##STR55## and theresulting four stereoisomers may be designated as the (4R,6S), (4S,6R),(4R,6R) and (4S,6S) stereoisomers. As used herein, the term"trans"-1,3dioxane is intended to include a mixture of (4R,6R) and(4S,6S) enantiomers while the term "cis"-1,3-dioxane is intended toinclude a mixture of (4R,6S) and (4S,6R) enantiomers. Since the mostpreferred enantiomer of the lactone compounds of Formula Ig hasfortuitously the same (4R,6S) stereoisomeric designation as the mostpreferred enantiomer of the 1,3-dioxane intermediates, the additionaldesignation of "trans" or "cis" is included to avoid any possibleconfusion.

The compounds of Formulae XXXVa and XXXVb may be prepared by thereaction of an aldehyde of Formula XXXVI with an ester of acetoaceticacid and then reacting a ketone or ketal with a compound of FormulaXXXVIII followed by hydrolysis of the resulting 1,3-dioxane of FormulaXXXIX and optionally resolving the acid of Formula XXXX, as shown inReaction Scheme 14. ##STR56##

In Reaction Scheme 14, R¹⁴ and R¹⁵ each are independently hydrogen, C₁₋₆alkyl or phenyl which is optionally substituted by one or two C₁₋₄alkyl, halogen, C₁₋₄ alkoxy or trifluoromethyl; R¹⁸ is a hydrolyzableester group, m is zero or 1 and R¹⁶ and R¹⁷ are as previously defined.The ketoester of Formula XXXVII may be prepared by the reaction of anester of acetoacetic acid with an aldehyde of Formula XXXVI byprocedures well-known to those skilled in the art in an inert organicsolvent such as tetrahydrofuran at temperatures of about 0° C. to about-78° C. in the presence of a base such as sodium hydride, lithiumdiisopropylamide and n-butyllithium.

The starting materials of Formula XXXVI wherein m=0 and m=1 are known ormay readily be prepared by known methods. The starting materials ofFormula XXXVI wherein m=1 may also be prepared by the reaction ofcompounds of Formula XXXVI wherein m=0 with Wittig reagents such astriphenylphosphoranylidene acetaldehyde and other methods well-known inthe art. It should be appreciated by those skilled in the art that therelative configuration of the double bond (m=0) or double bonds (m=1) inthe starting materials of Formula XXXVI may be trans, cis or mixturesthereof. The relative amounts of each geometric isomer (E) or (Z) willbe determined by commercial availability or the reaction conditionsemployed in the preparation. In a specific example described herein, amixture containing mostly trans (E) isomer was employed. Even though asmall percent of the other isomer may be present throughout the seriesof reactions shown in Reaction Scheme 14, it should be evident to thoseskilled in the art that the relative amount of isomers is not criticalsince the double bond is oxidized and thereby removed in the ozonolysisreaction.

The ketoester of Formula XXXVII may be reduced to the dihydroxyester ofFormula XXXVIII by reduction of the ketone group with reducing agentswell-known in the art. Preferably, the reduction is carried out in astereospecific manner by a two-step stereospecific reduction in order tomaximize the production of the preferred erythro isomer of thedihydroxyester of Formula XXXVIII. The stereospecific reduction iscarried out with trisubstitutedalkylboranes, preferably triethylboraneor tri-n-butylborane, or alkoxydialkylboranes, preferablymethoxydiethylborane or ethoxydiethylborane [Tetrahedron Letters, 28,155 (1987)] at a temperature of about -70° C. to about ambienttemperature. The complex which is produced is then reduced with sodiumborohydride at a temperature of about -50° C. to about -78° C. in aninert organic solvent such as tetrahydrofuran, diethylether and1,2-dimethoxyethane, preferably tetrahydrofuran. The reduction is thencompleted by the addition of methanol with or without the addition ofaqueous hydrogen peroxide and buffer. Some of the compounds of FormulaXXXVIII are known and described in U.S. Pat. No. 4,248,889 (issued Feb.3, 1981) and U.S. Pat. No. 4,650,890 (issued Mar. 17, 1987).

The compounds of Formula XXXIX may be prepared from the compounds ofFormula XXXVIII by reacting a ketone such as 2-propanone, 3-pentanone,cyclopentanone and cyclohexanone in a suitable inert organic solvent,e.g. toluene, benzene or xylene at temperatures of about 20° C. to thereflux temperature of the solvent employed in the presence of a smallamount of organic, mineral or resin acid, e.g., p-toluenesulfonic acidand sulfuric acid and optionally removing the water which is formed witha drying agent, e.g., Na₂ SO₄, MgSO₄ and molecular sieves or byazeotropical removal with a Dean-Stark trap or similar apparatus. Thereaction of a compound of Formula XXXVIII with a ketone may also becarried out without solvent. Alternatively, the above reaction ofcompounds of Formula XXXIX may be carried out with a ketal such as2,2-dimethoxypropane, 1,1-dimethoxycyclohexane and the like.

The compounds of Formula XXXVa wherein R¹⁹ is a hydrolyzable estergroup, and preferably, C₁₋₄ alkyl may be prepared from the correspondingcompounds of Formula XXXIX by oxidation of the olefinic group to analdehyde group using conventional means. Alternatively, a compound ofFormula XXXIX is first hydrolyzed by basic hydrolysis to a compound ofFormula XXXX which is then oxidized to give a compound of Formula XXXVawherein R¹⁹ is hydrogen. A particularly convenient oxidation method isthe reaction of a compound of Formula XXXIX or XXXX in an inert organicsolvent such as methanol, ethyl acetate and methylene chloride withozone at temperatures of about -50° C. to about -78° C. When thereaction with ozone is complete as evidence by the color of the reactionmixture, the intermediate ozonide is decomposed by the addition of amild reducing agent, e.g., dimethyl sulfide and triphenylphosphine togive the desired aldehyde of Formula XXXVa.

The preferred cis-(4R,6S) aldehydes of Formula XXXVb may be preparedfrom the corresponding racemic acid of Formula XXXX by conventionalresolution methods such as fractional crystallization after theintroduction of a suitable salt-forming group. The resulting mixture ofdiastereoisomeric salts which is formed with an optically activesalt-forming agent such as (1S,2R)-ephedrine and α-methylbenzylamine isseparated and the separated resolved salt is converted to a compound ofFormula XXXVb. Preferably, the salt-forming agent is (1S,2R)-ephedrineand the method of separation is by fractional crystallization. Theresolution may be carried out in an inert organic solvent, andpreferably, in a mixture of hydrocarbon-alcohol solvents, e.g.,hexane-methanol mixture, in which the resolved salt may crystallize fromthe solution. If it is desired, the acid of Formula XXXVb may beconverted to a salt wherein R¹⁹ is a metal cation or to a hydrolyzableester group wherein R¹⁹ is C₁₋₄ alkyl.

The most preferred antihypercholesterolemic compounds of FormulaeXXXXIVa, XXXXIVb and Ig may be prepared from a compound of Formula XXXVaor XXXVb by the general procedures described herein, and in U.S. patentapplication Ser. No. 156,865, filed Feb. 18, 1988 (concurrently) byWilliam T. Han and John J. Wright. The use of the aldehydes of FormulaXXXVa is shown in Reaction Scheme 15 and the use of the chiral aldehydesof Formula XXXVb is shown in Reaction Scheme 16. ##STR57##

In Reaction Schemes 15 and 16, R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶, R¹⁷ and R¹⁹are previously defined and Z is ##STR58## in which R¹² is C₁₋₄ alkyl,R¹³ is phenyl which is unsubstituted or substituted by one or two C₁₋₄alkyl or chloro substituents and X is bromo, chloro or iodo. Thepreparation of the phosphonium salt of Formula XVII and the phosphonateof Formula XVIIa is described herein, and in Scheme 13. The reaction ofa compound of Formula XVII or XVIIa with a compound of Formula XXXVa orFormula XXXVb to produce a compound of Formula XXXXII or XXXXIII,respectively, wherein R¹⁹ is C₁₋₄ alkyl may be carried out in an inertorganic solvent such as tetrahydrofuran and N,N-dimethylformamide in thepresence of a strong base such as n-butyllithium at a temperature ofabout -50° C. to about -78° C. When the reaction of a compound ofFormula XVII or XVIIa is carried out with a compound of Formula XXXVa orXXXVb wherein R¹⁹ is hydrogen, it is preferred to use two equivalents ofa strong base such as n-butyllithium. Alternatively, the salt of acompound of Formula XXXVa or XXXVb may be prepared which is then treatedwith a compound of Formula XVII or XVIIa and a strong base. The methodsof addition, salt formation and ylide preparation are well-known tothose skilled in the art. The tetrazole compounds of Formula XXXXII orXXXXIII may be readily deprotected by well-known procedures such as mildacid, e.g., 0.2N HCl and 0.5N HCl in an inert organic solvent such astetrahydrofuran to produce the erythro compounds of Formula XXXXIVa orthe (3R,5S) compounds of Formula XXXXIVb which may then be converted tothe trans compounds of Formula Ig or (4R,6S) compounds of Formula Ig ina conventional manner well-known to those skilled in the art.

In still another aspect, the present invention provides prodrug forms ofthe preferred embodiment of the compounds of Formula I having thestructure ##STR59## wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previouslydefined, R²⁰ is hydrogen, C₁₋₆ alkyl or a metal cation and R²¹ is C₁₋₆alkyl, hydroxy C₁₋₆ alkyl, phenyl C₁₋₆ alkyl, hydroxyphenyl C₁₋₆ alkyl,amido C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl C₁₋₆ alkyl, imidazol-4-yl-C₁₋₆alkyl, C₁₋₆ alkylthio C₁₋₆ alkyl, or indol-3-yl C₁₋₆ alkyl in which theamido ester moiety is in the L-configuration.

In the compounds of Formula XXXXV, R¹, R², R³, R⁴, R⁵ and R⁶,independently, are preferably hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄alkoxy. More preferably, R¹ and R⁴ are hydrogen and R², R³, R⁵, and R⁶,independently, are hydrogen, fluoro, chloro, methyl or methoxy, and mostpreferably, R¹ and R⁴ are hydrogen and R², R³, R⁵ and R⁶, independently,are hydrogen, fluoro, methyl or methoxy. It is preferred that R²⁰ ishydrogen, C₁₋₂ alkyl or a metal cation. Preferably, R²¹ is C₁₋₄ alkyl,hydroxy C₁₋₂ alkyl, phenyl C₁₋₂ alkyl, hydroxyphenyl C₁₋₂ alkyl, amidoC₁₋₂ alkyl, C₁₋₂ alkoxycarbonyl C₁₋₂ alkyl, imidazol-4-yl C₁₋₂ alkyl,C₁₋₂ alkylthio C₁₋₂ alkyl or indol-3-yl C₁₋₂ alkyl in which the amidoester moiety is in the L-configuration. The stereoisomer of FormulaXXXXV having two asymmetric carbon atoms bearing the hydroxy groups inthe 3 and 5 position is preferably erythro and the most preferredstereoisomer is the (3R,5S) of Formula XXXXV.

The compounds of Formula XXXXV are prodrugs of the compounds of thepresent invention which are bioconverted following systemicadministration to be useful antihypercholesterolemic agents. The mostpreferred amido acid and amido ester derivatives of Formula XXXXV may beprepared from the (4R,6S) compounds of Formula If by the generalprocedure described in U.S. Pat. No. 4,678,806 (July 7, 1987) to Baldwinet al. and illustrated for the most preferred isomer in Reaction Scheme17. ##STR60##

In Reaction Scheme 17, R¹, R², R³, R⁴, R⁵, R⁶ and R²¹ are as previouslydefined and R⁹ is a hydrolyzable ester group. The compounds of FormulaIf which are described herein may be reacted with an ester of theappropriate L-amino acid in an inert organic solvent such astetrahydrofuran and preferably at the reflux temperature of the solventto produce a compound of the Formula XXXXVI. If it is desired to preparecompounds of the Formula XXXXV wherein R²⁰ is hydrogen or a metalcation, then the compound of Formula XXXXV may be hydrolyzed undercontrolled conditions with dilute alkali hydroxide such as sodiumhydroxide and potassium hydroxide in a conventional manner to produce acompound of Formula XXXXV.

The prodrug compounds of the present invention may be administeredparenterally or, preferably, orally in the form of a capsule, a tablet,an injectable preparation or in a form described herein for thecompounds of present invention. The oral dosage unit will contain theactive ingredient in an amount of from about 0.01 mg/kg to about 10mg/kg body weight to be administered in equal doses from one to fourtimes a day.

The compounds of Formula XXXXV may also be co-administered withpharmaceutically acceptable non-toxic cationic polymers capable ofbinding bile acids in a non-reabsorbable form in the gastrointestinaltract, e.g., cholestyramine, colestipol and poly[methyl-(3-trimethylaminopropyl)iminotrimethylene dihalide]. Therelative amounts of polymer to compounds of this invention is betweenabout 10:1 to about 10,000:1.

DESCRIPTION OF SPECIFIC EMBODIMENTS

In the following examples, all temperatures are given in degreesCentigrade. Melting points were recorded on a Thomas-Hoover capillarymelting point apparatus and boiling points were measured at specificpressures (mm Hg) and both temperatures are uncorrected. Proton magneticresonance (¹ H NMR) spectra were recorded on a Bruker AM 300, Bruker WM360 or Varian T-60 CW spectrometer. All spectra were determined inCDCl₃, DMSO-d₆ or D₂ O unless otherwise indicated and chemical shiftsare reported in δ units downfield from the internal standardtetramethylsilane (TMS) and interproton coupling constants are reportedin Hertz (Hz). Splitting patterns are designated as follows: s, singlet;d, doublet, t, triplet; q, quartet; m, multiplet; br, broad peak; anddd, doublet of doublet. Carbon-13 nuclear magnetic resonance (¹³ C NMR)spectra were recorded on a Bruker AM 300 or Bruker WM 360 spectrometerand were broad band proton decoupled. All spectra were determined inCDCl₃, DMSO-d₆ or D₂ O unless otherwise indicated with internaldeuterium lock and chemical shifts are reported in δ units downfieldfrom tetramethylsilane. Infrared (IR) spectra were determined on aNicolet MX-1 FT spectrometer from 4000 cm⁻¹ to 400 cm⁻¹, calibrated to1601 cm⁻¹ absorption of a polystyrene film and are reported inreciprocal centimeters (cm⁻¹). Relative intensities are indicated asfollows: s (strong), m (medium) and w (weak). Optical rotations [α]_(D)²⁵ were determined on a Perkin-Elmer 241 polarimeter in CHCl₃ at theconcentrations indicated.

Gas chromatography-mass spectra (GC-MS) were determined on a Finnigan4500 Gas chromatography-quadruple mass spectrometer at ionizationpotential of 70 eV. Mass spectra were also recorded on a Kratos MS-50instrument utilizing the fast atom bombardment (FAB) technique. The massdata are expressed in the format: parent ion (M⁺) or protonated ion(M+H)⁺.

Analytical thin-layer chromatography (TLC) was carried out on precoatedsilica gel plates (60F-254) and visualized using UV light, iodine vaporsand/or staining with one of the following reagents: (a) methanolicphosphomolybdic acid (2%) and heating; (b) reagent (a) followed by 2%cobalt sulphate in 5M H₂ SO₄ and heating. Column chromatography, alsoreferred to as flash column chromatography, was performed in a glasscolumn using finely divided silica gel (32-63 m on silica gel-H) andpressures somewhat above atmospheric pressure with the indicatedsolvents. Ozonolysis reactions were done using a Welsbach ozonator styleT-23. All evaporations of solvents were performed under reducedpressure. As used herein, the term hexanes is a mixture of isomeric C₆hydrocarbons as specified by the American Chemical Society, and the term"inert" atmosphere is an argon or nitrogen atmosphere unless otherwiseindicated. 048974901

EXAMPLE 1 Ethyl 2-cyano-3,3-bis(4-fluorophenyl)-2-propenoate

A mixture of 20.0 g (92 mmoles) of 4,4'-difluorobenzophenone, 11.0 g (97mmoles) of ethyl cyanoacetate in a mixed solvent of 100 mL of drybenzene and 20 mL of glacial acetic acid containing a catalytic amountof β-alanine (0.9 g) was refluxed with separation of water using aDean-Stark water trap. Separation of water was rapid during the first 2hours (0.4 mL aqueous layer collected) but slower afterward. Azeotropicdistillation was continued for a period of 14 days. Analytical TLCeluted with 10% EtOAc in hexanes (v/v) (Merck plate, 0.25 mm Silicagel-F) showed two spots at R_(f) =0.2 (desired product) and at R_(f)=0.45 (4,4'-difluorobenzophenone starting material). Crude reactionmixture was washed with water (40 mL×2), and the combined aqueous washeswere extracted with EtOAc (150 mL×2). The organic layers were combined,dried over MgSO₄ and concentrated under reduced pressure to crystallizethe product as pale cubic crystals. The crude product was collected,washed with 1:1 EtOAc in hexanes (v/v) then recrystallized from 8:1(hexanes:ethyl acetate v/v) to give 16.2 g (56.3%) of analytical puretitle compound; m.p.=114°-116° C.

IR (KBr) ν_(max) : 3000 (s), 2225 (s), 1931 (vs), 1605 (s), 1513 (s),1250 (s), 844 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) ⊕ : 1.19 (3H, t, J=7.1 Hz), 4.18 (2H, q, J=7.1 Hz),7.08-7.15 (6H, m), 7.40-7.42 (2H, m);

¹³ C NMR (CDCl₃) δ : 13.75, 62.27, 104.05, 116.69, 115.53 (d, ² J_(C-F)=22.7 Hz), 115.88 (d, ² J_(C-F) =22.7 Hz), 131.64 (d, ³ J_(C-F) =9.1Hz), 132.66 (d, ³ J_(C-F) =9.1 Hz), 134.25, 134,31, 134.36, 164.01 (d, ¹J_(C-F) =252.9 Hz), 164.52 (d, ¹ J_(C-F) =254.0 Hz), 166.65 ppm.

Anal. Calcd. for C₁₈ H₁₃ NO₂ F₂ : C, 69.01; H, 4.15; N, 4.47. Found: C,68,91; H, 4.15; N, 4.62.

EXAMPLE 2 Ethyl3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate

A dry 50 mL round bottom flask was charged with 5.0 g (16.0 mmoles) ofethyl 2-cyano-3,3-bis(4-fluorophenyl)-2-propenoate followed by 8.0 g(24.1 mmoles) of azidotributylstannane [prepared by the proceduredescribed in Rev. Trav. Chim., 81, 202-5 (1962)] and 2.0 mL of reagentgrade toluene. The heterogenous mixture was stirred and heated to reflux(110° C.) in an oil bath behind a safety shield. The solid startingmaterial dissolved gradually forming a pale yellowish thick syrup andthe homogenous mixture was stirred and refluxed for 20 hours. AnalyticalTLC eluted with 20% MeOH in CHCl₃ (v/v) showed the product at R_(f)=0.26 (streak). The crude reaction mixture was diluted with an equalvolume of diethyl ether and was poured into a vigorously stirringsaturated aqueous solution of KF (200 mL containing 2 mL of 48% HBF₄). Avoluminous precipitate (Bu₃ SnF) was observed soon after mixing and thehydrolysis was allowed to proceed for 16 hours. The suspension wasfiltered and the filtrate was extracted with EtOAc (100 mL×2). Theorganic layers were combined, dried over MgSO₄ and concentrated underreduced pressure. The title compound crystallized from the concentrateyielding 4.54 g (77%) of white analytical pure material; m.p.=159-161°C.

IR (KBr) ν_(max) : 3438 (br), 1713 (vs), 1600 (s), 1510 (s), 1238 (s),841 (s) cm⁻¹.

¹ H NMR (CDCl₃) δ : 0.92 (3H, t, J=7.6 Hz), 3.98 (2H, q, J=7.6 Hz),7.3-6.7 (8H, m), 10 (1H, v.br.);

¹³ C NMR (CDCl₃) δ : 166.52, 163.54 (d, ¹ J_(C-F) =250.7 Hz), 163.46,(d, ¹ J_(C-F) =262.7 Hz), 157.14, 136.40, 134.74, 131.71 (d, ² J_(C-F)=67.2 Hz), 131.59 (d, ² J_(C-F) =66.4 Hz), 115.75 (d, ³ J_(C-F) =18.9Hz), 115.45 (d, ³ J_(C-F) =18.1 Hz) 62.11, 13.47 ppm.

Anal. Calcd. for C₁₈ H₁₄ F₂ N₄ O₂ : C, 60.27; H, 4.06; N, 15.50. Found:C, 60.67; H, 3.96; N, 15.72.

EXAMPLE 3 Ethyl3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoate andethyl 3,3-bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenoateA. Ethyl3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoate

To a solution of 0.5 g (1.40 mmoles) of ethyl3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate in 100 ml ofdry benzene at 45° C. under argon was added sodium hydride 100 mg (60%in mineral oil 2.5 mmoles) in one single portion. The greyish suspensionwas stirred at 45° for 30 minutes then 1 mL (16.1 mmoles) of methyliodide was added, and the flask was sealed with a rubber stopper.Alkylation was allowed to proceed at 40-45° C. for a total of four days.Analytical TLC eluted twice with 20% EtOAc in hexanes showed inly twoisomeric products at R_(f) =0.16 (major isomer 4) and R_(f) =0.22 (minorisomer 5). The crude reaction mixture was washed with an equal volume ofwater and the aqueous phase was back extracted once with 50 mL ofdiethyl ether. The organic layers were combined, dried over MgSO₄ andconcentrated under reduced pressure to give crude product. The productratio for the 1-isomer:2-isomer was determined to be about 5.6:1 by gaschromatography and by ¹ H NMR spectroscopy.

The crude product mixture which was prepared as described above (5.0 g)was taken into 20 mL of hot ethyl acetate to which was added 40 mL ofhot hexanes. The clear solution was allowed to cool slowly to roomtemperature to give 2.16 g (52%) of the title compound as colorlesslarge needles; m.p.=144-145° C.

IR (KBr) ν_(max) : 1713 (vs), 1600 (s), 1513 (s), 1325 (s), 1163 (s),838 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 7.4-6.8 (8H, m), 4.06 (2H, q, J=7.1 Hz) 3.68 (3H,s), 1.00 (3H, t, J=7.1 Hz);

¹³ C NMR (CDCl₃) δ : 165.44, 163.6 (d, ¹ J_(C-F) =250.7 Hz), 163.4 (d, ¹J_(C-F) =252.9 Hz) 156.85, 152.37, 135.88, 131.32 (d, ³ J_(C-F) =8.3Hz), 115.94 (d, ^(g) J_(C-F) =21.9 Hz), 115.64 (d, ² J_(C-F) =22.7 Hz),61.84, 33.76, 13.59 ppm;

Anal. Calcd. for C₁₉ H₁₆ F₂ N₄ O₂ : C, 61.62; H, 4.35; N, 15.13, Found:C, 61.63; H, 4.45; N, 15.21.

B. Ethyl3,3-bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenoate

The residue (2.0 g) obtained from the filtrate of the recrystallizationin Step A (containing about equal portions of the 1- and 2-methylisomers) was purified by silica gel (35 g) chromatography. Theappropriate fractions were collected, and evaporated to give crystallineproduct. Recrystallization from hexanesethyl acetate mixture (9:1; v/v)yielded the title compund; m.p.=117°-118° C.

IR (KBr) ν_(max) : 1713 (vs), 1600 (s), 1506 (s), 1250 (sh), 1225 (vs),850 (m) cm⁻¹ ;

¹ H NMR(CDCl₃) δ : 7.4-6.8 (8H, m), 4.20 (3H, s), 406 (2H, q, J=7.1 Hz),0.99 (3H, t, J=7.1 Hz);

¹³ C NMR (CDCl₃) δ : 167.12, 163.02 (d, ¹ J_(C-F) =272.6 Hz), 163.03 (d,¹ J_(C-F) =225.7 Hz), 162.80, 152.59, 137.03 (d, ⁴ J_(C-F) =4 Hz),135.96 (d, ⁴ J_(C-F) =3 Hz), 131.94 (d, ³ J_(C-F) =8.3 Hz), 131.08 (d, ³J_(C-F) =8.3 Hz), 120.48, 115.37 (d, ² J_(C-F) =21.9 Hz), 115.26 (d, ²J_(C-F) =22.7 Hz) 61.41, 39.40, 13.61 ppm;

Anal. Calcd. for C₁₉ H₁₆ F₂ N₄ O₂ : C, 61.62; H, 4.35; N, 15.13. Found:C, 61.77; H, 4.44; N, 15.38.

EXAMPLE 43,3-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoic acid

To a solution of ethyl3,3-bis(4-fluorophenyl-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoate 4.0 g(10.8 mmoles) in a mixture containing 20 mL of methanol and 20 mLtetrahydrofuran at 0° C. (ice-water bath) was added a solution of 3Molar lithium hydroxide in H₂ O (9 mL). Saponification reaction wasallowed to proceed overnight (ca. 16 hours) forming a clear homogeneoussolution. Analytical TLC eluted twice with 30% ethyl acetate in hexanes(v/v) showed the desired product at the origin. Crude reaction mixturewas made acidic by adding 10 mL of 3 Molar HCl solution and the organicmaterial was extracted twice into ethyl acetate (20 mL×2). Organiclayers were combined, dried over MgSO₄ and concentrated under reducedpressure to give the product as a pale yellow solid. Recrystallizationfrom EtOAc-hexanes mixture (1:9; v/v) yielded 3.8 g (100%) of the titlecompound; m.p.=205-206° C.

IR (KBr) ν_(max) : 3438 (br), 2900 (br), 1725 (s), 1713 (s), 1600 (s),1501 (s), 1231 (vs), 1156 (s), 850 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 7.9-6.4 (8H, m), 3.68 (3H, s);

¹³ C NMR (CDCl₃) δ : 166.57, 163.3 d, ¹ J_(C-F) =249.9 Hz), 163.03 (d, ¹J_(C-F) =250 Hz), 155.68, 152.61, 135.58, 134.74, 131.75 (d, ³ J_(C-F)=8.3 Hz), 131.28 (d, ³ J_(C-F) =9.1 Hz) 117, 115.7 (d, ² J_(C-F) =22.6Hz), 115.4 (d, ² J_(C-F) =22.6 Hz), 33.6 ppm;

Anal. Calcd. for C₁₇ H₁₂ F₂ N₄ O₂ : C, 59.05; H, 3.53; N, 16.37. Found:C, 59.54; H, 3.58; N, 16.27.

EXAMPLE 53,3-Bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenoic Acid

The general procedure of Example 4 was repeated, except that the ethyl3,3-bis(4-fluorophenyl)- 2-(1-methyl-1H-tetrazol-5-yl)-2-propenoateutilized therein was replaced by ethyl3,3-bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenoate toyield after recrystallization from ethyl acetate-hexanes the titlecompound in essentially quantitative yield; mp=154°-155° C.

IR (KBr) ν_(max) : 3438 (br), 3000 (br), 1675 (s), 1600 (s), 1503 (s),1231 (s), 1225 (s), 1150 (s), 838 (s) cm⁻¹ ;

¹ H NMR (CDCl₃ -DMSO-d₆) δ : 7.33-7.28 (2H, m), 7.05-6.96 (4H, m), 6.87(2H, t, J=8.64 Hz), 4.23 (3H, s);

¹³ C NMR (CDCl₃ -DMSO-d₆) δ : 168.70, 163.05 (d, ¹ J_(C-F) =248.4 Hz),163.07, 162.66 (d, ¹ J_(C-F) =249.9 Hz), 151.81, 136.81, 136.22, 131.83(d, ³ J_(C-F) =8.3 Hz), 131.20 (d, ³ J_(C-F) =8.3 Hz), 121.04, 115.24(d, ² J_(C-F) =21.9 Hz), 115.14 (d, ² J_(C-F) =21.1 Hz) ppm;

Anal. Calcd. for C₁₇ H₁₂ F₂ N₄ O₂ : C, 59.65; H, 3.53; N, 16.37. Found:C, 59.56; H, 3.59; N, 16.36.

EXAMPLE 63,3-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal A.3,3-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenylchloride

To a solution of dry (0.1 mmHg at 80° C.)3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)2-propenoic acid3.8 g (11.0 mmoles) in 20 mL of dry methylene chloride was added 4 mL(46.0 mmoles) of purified oxalyl chloride (redistilled over CaH₂) in onesingle portion. The reaction mixture was warmed gradually to refluxtemperature for two hours. the mixture was evaporated under reducedpressure to remove volatile solvent, then excess oxalyl chloride wasremoved under vacuum (20 mmHg) at ambient temperature for 2 hours andunder high vacuum (0.1 mmHg) at 50° C. for 16 hours to give the titlecompound.

B. 3,3-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenol

The acyl chloride prepared in Step A was dissolved into 150 mL oftetrahydrofuran and was chilled to -78° C. under argon. To this palebrownish solution at -78° C. was added 8.0 mL lithium aluminum hydridein THF solutions (1.0 Molar). Analytical TLC after 15 minutes showedonly one mobile spot at R_(f) =0.23 (50% EtOAc in hexanes v/v). Thecrude reaction mixture was diluted with 2M H₂ SO₄ (20 ml). The aqueouslayer was extracted with ethyl acetate (40 mL×2). Organic layers werecombined, dried over MgSO₄ and concentated under reduced pressure togive 3.64 g (100%) of the title compound. The crude allylic alcohol wasused immediaely in the next step without further purification. MS (CI):m/e=328 for (M+H)⁺ ;

IR (KBr) ν_(max) ; 3388 (v.br), 1600 (s), 1501 (s), 1225 (s), 1156 (s),838 (s), 750 (s), cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 7.5-6.9 (8H, m), 4.52 (2H, br), 3.42 (3H, s), 3.75(1H, br, D₂ O exchangeable);

¹ H NMR (DMSO-d₆) δ : 7.5-6.9 (8H, m), 5.23 (1H, t, J=5.5 Hz), 4.27,(2H, d J=5.5 Hz), 354 (3H, s) ppm;

C. 3,3-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

To a vigorously stirred solution of the crude allylic alcohol 3.64 g[prepared in Step B] in 40 mL of methylene chloride at room temperaturewas added 2.6 g (12.0 mmoles) of pyridinium chlorochromate in one singleporion. Analytical TLC immediately afterward showed about 50% of productat R_(f) =0.34 along with the starting material at R_(f) =0.14 (elutedwith 50% EtOAc:Hexanes v/v). The oxidation was allowed to proceed atroom temperature for a total of 16 hours, during which all the startingmaterial was consumed and TLC showed only product. The crude reactionsuspension was filtered through a bed of silica gel, washed with oneliter of 10% (v/v) ethyl acetate in hexanes and one liter of 20% (v/v)ethyl acetate in hexanes. The desired product crystallized uponconcentration under reduced pressure to give 2.7 g (74%) of the titlecompound; m.p.=141°-142° C. MS (CI): m/e=326 for (M+H)⁺ ;

IR (KBr) ν_(max) : 3075 (m), 2875 (m), 1675 (s), 1600 (s), 1501 (s),1238 (s), 1156 (s), 850 (s), 750 (s), cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 9.63 (1H, s), 9.5-6.9 (8H, m), 3.74 (3H, s),

¹³ C NMR (CDCl₃) δ : 188.92, 165.44, 164.68 (d, ¹ J_(C-F) =254.4 Hz),164.10 (d, ¹ J_(C-F) =255.9 Hz), 151.34, 134.31, 133.77 (d, ³ J_(C-F)=8.3 Hz), 132.69, 132.23 (d, ³ J_(C-F) =7.5 Hz) 123.70, 116.26 (d, ²J_(C-F) =21.9 Hz), 116.18 (d, ² J_(C-F) =22.7 Hz), 34.10 ppm;

Anal. Calcd. for C₁₇ H₁₂ F₂ N₄ O: C, 62.58; H, 3.71; N, 17.17. Found: C,62.41; H, 3.85; N, 16.98.

EXAMPLE 73,3-Bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenal

The general procedure of Steps A, B, and C of Example 6 was repeated,except that the3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoic acidutilized in Step A was replaced by3,3-bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenoic acid[prepared in Example 5] to yield the title compound as a gummy solid in76% overall yield. MS (CI): m/e=326 for (M+H)⁺.

IR (KBr) ν_(max) : 2863 (m), 2750 (w), 1681 (s), 1600 (s), 1503 (s),1225 (s), 1156 (s), 838 (s), 752 (s), cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 9.65, 7.34-7.30 (2H, m), 7.15 (2H, t, J=8.5 Hz),7.01-6.96 (2H, m), 6.88 (2H, t, J=8.4 Hz), 4.29 (3H, s);

¹³ C NMR (CDCl₃) δ : 190.08, 164.30 (d, ¹ J_(C-F) =254.4 Hz), 163.5 (d,¹ J_(C-F) =252.17 Hz), 163.20, 161.37, 135.55, 133.49, 133.66 (d, ³J_(C-F) =7.6 Hz), 132.38 (d, ³ J_(C-F) =9.1 Hz), 131.40, 127.54, 115.86(d, ² J_(C-F) =26.4 Hz), 115.57 (d, ² J_(C-F) =28.7 Hz), 39.55 ppm;

Anal. Calcd. for C₁₇ H₁₂ F₂ N₄ O: C, 62.58; H, 3.71; N, 17.17. Found: C,62.27; H, 4.22; N, 15.83.

EXAMPLE 85,5-Bis(4-fluorophenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal

To a dry mixture of3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal 0.70 g(2.1 mmoles) and triphenylphosphoranylidene acetaldehyde 0.72 g (2.5mmoles) under argon at ambient temperature was added 20 mL of drybenzene. The suspension was warmed to reflux temperature under an argonatmosphere and the reaction was allowed to proceed at reflux temperaturefor 30 minutes. Analytical TLC eluted four times with 20% ethyl acetatein hexanes (v/v) showed only one spot for product at R_(f) =0.15. Thecrude reaction mixture was poured on a silica gel column saturated withhexanes. The desired product was eluted with 1.5 liters of 20% EtOAc inhexanes (v/v) to give 0.67 g (89%) of the title compund which appearshomogeneous by TLC.

¹ H NMR (CDCl₃) δ : 9.53 (1H, d, J=7.5 Hz), 7.47 (1H, d, J=15.7 Hz),7.4-8.8, m), 5.80 (1H, dd, J₁ =7.4 Hz, J₂ =15.7 Hz), 4.11 (2H, q, J=7.1Hz), 3.58 (3H, s), 1.26 (3H, t, J=7.1 Hz) ppm.

The proton NMR (300 MHz) of the above product showed that it containsabout 10% of7,7-bis(4-fluorophenyl)-6-(1-methyl-1H-tetrazol-5-yl)-2,4,6-heptatrienalas a side product which was not easily removed. This material was usedin the next preparation without further purification.

EXAMPLE 95,5-Bis(4-fluorophenyl)-4-(2-methyl-2H-tetrazol-5-yl)-2,4-pentadienal

The general procedure of Example 8 was repeated, except that the3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-proenal utilizedtherein was replaced by 0.67 g (21.0 mmoles) of3,3-bis(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-propenal[prepared in Example 7]. The reaction was carried out with 0.64 g (21.0mmoles) of triphenylphosphoranylidene acetaldehyde to yield 0.66 g(90.5%) of the title compound.

¹ H NMR (CDCl₃) δ : 9.57 (1H, d, J=6.8 Hz), 7.50 (1H, d, J=16.5 Hz),7.3-6.8 (8H, m), 5.94 (1H, dd, J=6.8, 16.5 Hz), 4.30 (3H, s) ppm.

EXAMPLE 10 Ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoateand ethyl11,11-bis(4-fluorophenyl)-5-hydroxy-10-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8,10-undecatrienoateA. Ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate

To a chilled suspension (0° C., ice-water bath) of NaH (0.64 g, 16.0mmoles) (60% in mineral oil) in 20 mL Of dry tetrahydrofuran under argonwas added ethyl acetoacetate 2.04 mL (16.0 mmoles) in 4 equal portions.The homogeneous clear solution was stirred at 0° C. for 30 minutesfollowed by the dropwise addition of 6.4 mL of 2.5 Molar n-BuLi (16.0mmoles) over a period of 15 minutes. The orange dianion solution wasstirred at 0° C. for an additional hour. The ice-water bath was replacedby an acetone-dry ice bath at -78° C. and the dianion was transferredvia a cannula into a tetrahydrofuran (20 mL) solution containing5,5-bis(4-fluorophenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal(2.82 g, 8.01 mmoles). Analytical TLC showed the major desired productat R_(f) =0.15 (50% EtAOc in hexanes) and a minor product at R_(f) =0.2.The crude reaction mixture was diluted with 40 mL of 1N HCl and theaqueous layer was extracted with ethyl acetate (50 mL×2). The organiclayers were combined, dried over MgSO₄ and concentrated under reducedpressure. The desired product was purified by flash silica gel columnchromatography eluted with 20% EtOAc in hexanes (v/v) to give 2.26 g(58.5%) of the title compound. MS (CI): m/e=483 for (M+H)⁺.

IR (KBr) ν_(max) ; 3450 (v.br), 1738 (s), 1725 (s), 1606 (s), 1513 (vs),1225 (s), 1163 (s), 844 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 7.4-6.8 (8H, m), 6.72 (1H, d, J=15.6 Hz), 4.63 (1H,m), 4.17 (2H, q, J=7.1 Hz), 4.13 (1H, m), 3.60 (3H, s), 3.52 (1H, d,J=3.9 Hz, D₂ O exchangeable), 3.47 (2H, s), 2.74 (2H, d, J=6.0 Hz), 1.26(3H, t, J=7.1 Hz) ppm;

¹³ C NMR (CDCl₃) δ : 164.21, 135.98, 132.34 (d, ³ J_(C-F) =8.3 Hz),131.45 (d, ³ J_(C-F) =9.1 Hz), 115.74 (d, ² J_(C-F) =21.9 Hz), 115.74(d, ² J_(C-F) =21.1 Hz), 100.86, 67.61, 61.58, 49.85, 49.07, 33.56,14.10 ppm.

B. Ethyl11,11-bis(4-fluorophenyl)-5-hydroxy-10-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8,10-undecatrienoate

The silica gel column from the above Step A was eluted further to givethe minor product (R_(f) =0.2). Repeated flash silica gel chromatographywith 20% EtOAc in hexanes as the eluting solvent yielded the titlecompound.

¹ H NMR (CDCl₃) δ : 7.4-7.1 (4H, m), 6.9-6.8 (4H, m), 6.58 (1H, d,J=15.5 Hz), 6.31 (1H, dd, J=10.7, 15.0 Hz), 5.80, 1H, dd, J=10.7, 15.4Hz), 5.66 (1H, dd, J=5.5, 15.1 Hz), 4.64 (1H, m), 4.18 (2H, q, J=6.9Hz), 3.58 (3H, s) 3,46 (2H, s), 3.02 (1H, m), 2.75-2.72 (2H, m), 1.27(3H, t, J=6.9 Hz) ppm.

EXAMPLE 11 Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate(2.19 g, 4.53 mmoles) (dried under high vacuum at 30° C. for 48 hours)in 40 mL of anhydrous tetrahydrofuran at 0° C. (ice-water bath) underargon was added triethyl borane solution in tetrahydrofuran (4.8 mL, 4.8mmoles) in one single portion. The mixture was stirred under argon for atotal of one hour. The cooling ice-water bath was replaced with anacetone-dry ice bath and to the reaction mixture was added NaBH₄ (0.20g, 5.3 mmoles) in one portion. The reaction suspension was stirred at-78° C. for two hours forming a clear homogeneous pale yellow solution.The crude reaction mixture was diluted with 40 mL of 1N HCl followed byextractions with EtOAc (40 mL×2). The organic layers were combined,dried over MgSO₄ and concentrated under reduced pressure to give theproduct as a thick syrup, it was further diluted with 300 mL of methanoland the solution was allowed to stand at room temperature for 16 hoursbefore evaporation under reduced pressure. The crude product waspurified by flash silica gel column chromatography using 2 liters of 30%EtOAc in hexanes as the eluting solvent. The appropriate fractions werecollected and evaporated to give 1.48 g (68%) of the title compound. MS(CI): m/e=485 for (M+H)⁺ ;

IR (KBr) ν_(max) : 3438 (s), 1734 (s), 1600 (s), 1513 (s), 1225 (s),1163 (s), 844 (s), cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.4-7.3 (4H, m) 7.04 (2H, t, J=8.9 Hz), 6.9-6.7(2H, m), 6.52 (1H, dd, J=1, 15.2 Hz), 5.16 (1H, dd, J=5.6, 15.7 Hz),4.89 (1H, d, J=4.8 Hz), 4.72 (1H, d, J=5.5 Hz) 4.13 (1H, m), 4.04 (2H,q, J=7.2 Hz), 3.85 (1H, m), 3.75 (3H, s), 2.42, (1H, dd, J=4.6, 15 Hz),2.28 (1H, dd, J=8.3, 15 Hz), 5.5 (1H, m), 4.2 (1H, m), 1.17 (3H, t,J=7.2 Hz);

¹³ H NMR (DMSO-d₆) δ : 171.02, 163.51, 163.05, 153.03, 145.34, 139.46,136.34, 132.2 (d, ³ J_(C-F) =8.3 Hz), 131.0 (d, ¹³ J_(C-F) =9.1 Hz),125.14, 121.64, 115.41 (d, ² J_(C-F) =20.4 Hz), 115.13, (d, ² J_(C-F)=21.1 Hz), 67.79, 64.76, 59.50, 44.10, 42.34, 33.44, 14.01 ppm;

Anal. Calcd. for C₂₅ H₂₆ F₂ N₄ O₄ : C, 61.98; H, 5.41; N, 11.56. Found:C, 61.51; H, 5.67; N, 11.12.

EXAMPLE 12 Sodium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadionate

To a solution of ethyl9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate(1.231 g, 2.54 mmoles) in 35 mL of tetrahydrofuran at 0° C. was added 1NNaOH solution 2.54 mL (1.0 equivalent) dropwise. The rate of additionshould be slow enough to prevent the reaction mixture from changingcolor into deep amber or reddish. The reaction mixture was stirred for30 minutes at 0° C. forming a clear homogeneous solution. The reactionmixture was allowed to warm to ambient temperature and saponificationwas allowed to proceed for an additional hour. Analytical TLC elutedwith 20% MeOH in CHCl₃ (v/v) showed the desired product at R_(f) =0.2.Most of the organic solvent was evaporated at approximately 10° underreduced pressure (20 mmHg). The resulting thick syrup was diluted with 4mL of water and then the solution was lyophilized at 0.01 mmHg to give1.126 g (100%) of the title compound as a sodium salt which appears tocontain about one mole of water; m.p.>100° C. decomposed.

IR (KBr) ν_(max) : 3400 (v.br), 1600 (s), 1575 (s), 1513 (s), 1438 (s),1404 (s), 1225 (s), 1156 (s), 838 (s) cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.3-7.4 (4H, m), 7.06 (1H, br, D₂ O exchangeable),7.00-7.06 (2H, m), 6.87-6.91 (2H, m), 6.49 (1H, d, J=15.7 Hz), 5.13 (1H,dd, J=5.4, 15.7 Hz), 5.05 (1H, br, D₂ O exchangeable), 4.14 (1H, m),3.74 (3H, s), 3.62 (1H, m), 1.99 (1H, dd, J=3.7, 13.5 Hz), 1.80 (1H, dd,J=8.5, 13.5 Hz), 1.43 (1H, m), 1.30 (1H, m);

¹³ C NMR (DMSO-d₆) δ : 175.87, 161.85 (d, ¹ J_(C-F) =246.1 Hz), 161.37(d, ¹ J_(C-F) =246.9 Hz), 153.08, 144.97, 139.88, 136.40, 135.51, 132.22(d, ³ J_(C-F) =8.3 Hz), 130.97 (d, ³ J_(C-F) =8.3 Hz). 124.66, 121.74,115.42 (d, ² J_(C-F) =21.9 Hz), 115.12, (d, ² J_(C-F) =23.4 Hz), 68.23,65.71, 44.50, 43.55, 33.45 ppm;

Anal. Calcd. for C₂₃ H₂₁ F₂ N₄ O₄ Na H₂ O: C, 55.64; H, 4.67; N, 11.28.Found: C, 55.24; H, 4.65; N, 10.85.

EXAMPLE 13Trans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahdro-4-hydroxy-2H-pyran-2oneA.(±)-Erythro-9,9-Bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid

To a solution of ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate(0.64 g, 1.32 mmoles) in 25 mL of tetrahydrofuran at 0° C. was treatedwith 1.32 mL of 1.0 Molar NaOH solution. The pale yellow suspension wasstirred at 0° C. for two hours forming a clear pale yellow solution. Thecrude reaction mixture was diluted with 5 mL of aqueous HCl (2N)solution and organic material was extracted into ethyl acetate (40mL×2). The organic extracts were combined, dried over MgSO₄ andconcentrated under reduced pressure to give a pale yellow gum. The crudedihydroxy acid was rigorously dried under high vacuum (0.01 mm Hg atroom temperature for 24 hours) before submitting for the next step.

B.Trans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one

The dry acid from the above Step A was dissolved in 100 mL of drymethylene chloride under argon at room temperature followed by theaddition of 1.7 g (4.0 mmoles) of1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluenesulphonate. Lactonization was complete in less than 15minutes as indicated by analytical TLC (R_(f) =0.12) eluted three timeswith 50% ethyl acetate in hexanes, Most of the solvent was evaporatedunder reduced pressure and the residue was washed with water (40 mL)followed by extractions with ethyl acetate (40 mL×2). The organic layerswere combined, dried over MgSO₄ and concentrated under reduced pressureto give 0.54 g (89.7%) of the product. A pure sample of the product wasobtained by passing through a short bed of silica gel eluted with 40%ethyl acetate in hexanes (v/v) to give the title compound which appearsto contain about two moles of water. MS (CI): m/e=438 for (M+H)⁺ ;

IR (KBr) ν_(max) : 3425 (br), 1738 (v.s.), 1600 (s), 1513 (s), 1225(vs), 1156 (s), 1038 (s), 838 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 7.26-7.21 (2H, m), 7.14 (2H, d, J=8.7 Hz), 6.86 (4H,d, J=6.8 Hz), 6.72 (1H, dd, J=0.8, 15.6 Hz), 5.34 (1H, dd, J=7.1, 15.6Hz), 5.18 (1H, m), 4.37 (1H, m), 3.57 (3H, s), 2.68 (1H, dd, J=4.5, 18Hz), 2.60 (1H, ddd, J=3.63, 2.5, 18 Hz), 2.44 (1H, d, J=2.6 H₂, D₂ Oexchangeable), 2.00 (1H, dt, J=18, 1.7 Hz), 1.79 (1H, td, J=2.7, 18 Hz)ppm;

¹³ C NMR (CDCl₃) δ : 169.20, 163, 162.5, 153.20, 148.81, 135.61, 134.95,132.45 (d, ³ J_(C-F) =8 Hz), 132.52, 131.51, (d, ³ J_(C-F) =8 Hz),130.04, 120.44, 115.95, (d, ² J_(C-F) =21.9 Hz), 115.83 (d, ² J_(C-F)=21.9 Hz), 75.67, 62.54, 38.58, 35.58, 33.64 ppm;

Anal. Calcd. for C₂₃ H₂₀ F₂ N₄ O₃ 2H₂ O: C, 58.22; H, 5.10; N, 11.81.Found: C, 59.06; H, 4.45; N, 11.25.

A sample of the above lactone was crystallized from cyclohexane-benzeneto give the title compound as a crystalline solid containing about onemole of benzene; m.p.=104°-106° C.

Anal. Calcd. for C₂₃ H₂₀ F₂ N₄ O₃ C₆ H₆ : C, 67.48; H, 5.07; N, 10.85.Found: C, 67.44; H, 5.23; N, 10.59

EXAMPLE 14 Ethyl(±)-erythro-9,9-(4-fluorophenyl)-3,5-dihydroxy-8-(2-methyl-2H-tetrazol-5-yl)-6,8-nonadienoateA. Ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-(2-methyl-2H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate

The general procedure of Example 10, Step A was repeated, except thatthe5,5-bis(4-fluorophenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienalutilized therein was replaced by 0.66 g (1.87 mmoles) of5,5-bis(4-fluorophenyl)-4-(2-methyl-2H-tetrazol-5-yl)-2,4-pentadienaland there was thereby produced 0.53 g (59%) of the title compound aftersilica gel chromatography.

B. Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-methyl-2H-tetrazol-5-yl)-6,8-nonadienoate

The product from the above Step A was treated with triethylborane andsodium borohydride following the general procedure described in Example11 to give 0.36 g (69.5%) of the title compound after purification bysilica gel chromatography.

¹ H NMR (CDCl₃) δ : 7.30-7.22 (2H, m), 7.07 (2H, t, J=6.7 Hz), 6.89-6.86(2H, m), 6.78 (2H, t, J=8.7 Hz), 6.66(1H, d, J=15.5 Hz), 5.39 (1H, dd,J=6.3, 15.5 Hz), 4.41 (1H, m), 4.2 (1H, m), 4.27 (3H, s), 4.18 (2H, q,J=7.1 Hz), 3.92 (1H, br, D₂ O exchangeable), 3.69 (1H, br, D₂ oexchangeable), 2.47-2.42 (2H, m), 1.66-1.58 (2H, m), 1.26 (3H, t, J=327.1 Hz);

¹³ C NMR (CDCl₃) δ : 172.29, 162.52 (d, ¹ J_(C-F) =249.9 Hz), 161.94 (d,¹ J_(C-F) =248.4 Hz), 145.74, 137.59, 137.33, 136.87, 132.37 (d, ³J_(C-F) =8.3 Hz), 131.69 (d, ³ J_(C-F) =8.3 Hz), 128.53, 124.90, 115.50(d, ² J_(C-F) =21.1 Hz), 115.2 (d, ² J_(C-F) =20 Hz), 72.11, 68.07,60.74, 42.52, 41.73, 39.42, 14.17 ppm.

EXAMPLE 15 Ethyl(±)-erythro-11,11-bis(4-fluorophenyl)-3,5-dihydroxy-10-(1-methyl-1H-tetrazol-5-yl)-6,8,10-undecatrienoateand Sodium(±)-erythro-11,11-bis(4-fluorophenyl)-3,5-dihydroxy-10-(1-methyl-1H-tetrazol-5-yl)-6,8,10-undecatrienoateA. Ethyl(±)-erythro-11,11-bis(4-fluorophenyl)-3,5-dihydroxy-10-(1-methyl-1H-tetrazol-5-yl)-6,8,10-undecatrienoate

The general procedure of Example 11 was repeated, except that the ethyl9,9-bis(4-fluorophenyl)5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate utilizedtherein was replaced by 0.12 g of ethyl11,11-bis(4-fluorophenyl)-5-hydroxy-10-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8,10-undecatrienoate[prepared in Example 10, Step B] and there was thereby produced 50 mg(42%) of the title compound after silica gel chromatography.

¹ H NMR (CDCl₃) δ : 7.4-6.8 (8H, m), 6.57 (1H, d, J=15.4 Hz), 6.29 (1H,dd, J=10.8, 15.1 Hz), 5.80 (1H, dd, J=10.7, 15.4 Hz), 5.07 (1H, dd,J=5.7, 15.1 Hz), 4.44 (1H, q, J=5.8 Hz), 4.24 (1H, m), 4.16 (2H, q,J=7.1 Hz), 3.83 (1H, br, D₂ O exchangeable), 3.65 (1H, br. D₂ Oexchangeable), 3.58 (3H, s), 2.47 (2H, d, J=6.3 Hz), 1.62 (2H, m), 1.28(3H, t, J=7.1 Hz);

¹³ C NMR (CDCl₃) δ : 172.43, 162.87 (d, ¹ J_(C-F) =257.46 Hz), 162.47(d, ¹ J_(C-F) =249.91 Hz), 153.45, 146.20, 138.62, 135.98, 135.50,133.98, 132.39 (d, ³ J_(C-F) =8.3 Hz), 131.48 (d, ³ J_(C-F) =8.3 Hz),131.18, 129.80, 129.16, 121.95, 115.75 (d, ² J_(C-F) =22.0 Hz), 115.67(d, ² J_(C-F) =22.0 Hz), 71.72, 68.34, 60.82, 42.45, 41.57, 33.54, 14.16ppm.

B. Sodium(±)-erythro-11,11-bis(4-fluorophenyl)-3,5-dihydroxy-10-(1-methyl-1H-tetrazol-5-yl)-6,8,10-undecatrienoate

The product from the above Step A was saponified by the generalprocedure described in Example 12 to produce the title compound inquantitative yield.

¹ H NMR (DMSO-d₆) δ : 7.5-6.8 (8H, m), 6.44 (1H, d, J=15.5 Hz), 6.17(1H, dd, J=11.4, 14.8 Hz), 5.7 (2H, m) 4.14 (1H, q, J=5.5 Hz), 3.7 (2H,br, D₂ O exchangeable), 3.67 (3H, s), 3.90 (1H, m), 2.02 (1H, d, J=11.7Hz), 1.84 (1H, dd, J=8.6, 14.4 Hz), 1.46 (1H, m), 1.29 (1H, m) ppm.

¹³ C NMR (DMSO-d₆) δ : 176.12, 152.81, 141.50, 136.25, 135.62, 134.02,132.35, 132.24, 127.72, 128.04, 122.17, 115.48 (d, ² J_(C-F) =21.9 Hz),115.19 (d, ² J_(C-F) =21.1 Hz), 68.31, 65.73, 44.59, 43.57, 33.40 ppm.

EXAMPLE 16Trans-6-[4,4-bis(4-fluorophenyl)-3-(2-methyl-2H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one

The general procedure of Example 13, Step A and Step B were repeated,except that the ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoateutilized therein was replaced by 370 mg of ethyl9,9-bis(4-fluorophenyl)-3,5-dihydroxy8-(2-methyl-2H-tetrazol-5-yl)-6,8-nonadienoate and there was therebyproduced 146 mg (44%) of the title compound after silica gelchromatography. MS (CI): m/e=439 for (M+H)⁺ ;

IR (KBr) ν_(max) : 3438 (v.br), 1731 (s), 1600 (s), 1503 (vs), 1219(vs), 1153 (s), 1056 (m), 1031 (m), 838 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 7.29-6.82 (8H, m), 6.69 (1H, d J=15.6 Hz), 5.44 (1H,dd, J=9.0, 15.6 Hz), 5.24 (1H, m), 4.27 (3H, s), 4.30 (1H, m), 4.21 (1H,s, D₂ O exchangeable), 3.69 (1H, br.s D₂ O exchangeable), 2.6-2.4 (2H,m), 2.1-1.7 (2H, m);

¹³ C NMR (CDCl₃) δ : 169.94, 162.70 (d, ¹ J_(C-F) =249.2 Hz), 162.12 (d,¹ J_(C-F) =249.9 Hz), 147.68, 147.47, 137.27, 136.11, 132.36, (d, ³J_(C-F) =8.3 Hz), 131.71 (d, ³ J_(C-F) =8.3 Hz), 131.17, 131.10, 130.88,128.62, 124.28), 115.52 (d, ² J_(C-F) =20.4 Hz), 114.95 (d, ² J_(C-F)=21.9 Hz), 76.16, 62.33, 39.49, 38.66, 35.99 ppm;

Anal. Calcd. for C₂₃ H₂₀ F₂ N₄ O₃ 2H₂ O: C, 58.22; H, 5.10; N, 11.81.Found: C, 58.92; H, 4.62; N, 11.21.

EXAMPLE 17 Sodium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-methyl-2H-tetrazol-5-yl)-6,8-nonadienoate

The general procedure of Example 12 was repeated, except that the ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6.8-nonadienoateutilized therein was replaced with ethyl9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-methyl-1H-tetrazol-5-yl)-6,8-nonadienoateand there was thereby produced after lyophilization a quantitative yieldof the title compound as a sodium salt which appears to contain aboutone mole of water.

IR (KBr) ν_(max) : 3413 (v.br), 1600 (s), 1575 (s), 1500 (s), 1400 (s),1219 (s), 1088 (s) cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.36-6.82 (8H, m), 6.50 (1H, d, J=15.5 Hz), 5.28(1H, dd, J=5.8, 15.5 Hz), 5.0 (1H, br, D₂ O exchangeable), 4.9 (1H, br.D₂ O exchangeable), 4.28 (3H, s), 4.13 (1H, d, J=5.94 Hz), 3.64 (1H, m),2.03 (1H, dd, J=3.6, 14.9 Hz), 1.85, (1H, dd, J=8.7, 14.9 Hz), 1.5-1.2(2H, m);

¹³ C NMR (DMSO-d₆) δ : 176.25, 103.18, 161.47, (d, ¹ J_(C-F) =240 Hz),143.15, 137.60, 136.40, 125.48, 115.12, 114.46, 68.52, 65.84, 44.61,43.55 ppm.

Anal. Calcd. for C₂₃ H₂₁ F₂ N₄ O₄ Na H₂ O: C, 55.64; H, 4.67; N, 11.29.Found: C, 55.22; H, 4.79; N, 11.21.

EXAMPLE 18 Phenylmethyl9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-5-oxo-6,8-nonadienoate

3,3-(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)prop-2-enal (2.50 g,7.7 mmoles), phenylmethyl 6-(dimethylphosphono)-3-hydroxy-5-oxohexanoate(3.93 g, 11 mmoles), and anhydrous lithium bromide (1.40 g) werecombined in acetonitrile, and treated with1,8-diazobicyclo-[5.4.0]undec-7-ene (1.2 mL, 8.0 mmoles). The mixturewas stirred under argon at 23° C. for 44 hours before concentrating invacuo. The residue was partitioned between CH₂ Cl₂ (50 mL) and ice coldH₃ PO₄ (100 mL). The organic layer was washed with water (2×50 mL),dried over anhydrous Na₂ SO₄, and evaporated to give 4.2 g of an orangefoam. The crude product was preabsorbed onto silica and flashchromatographed three times on a silica gel (10-40) column with 40%ethyl acetate/hexane as the eluting solvent to give 0.36 g of the titlecompound. MS (CI): m/e=545 for (M+ H)⁺ ;

IR (KBr) ν_(max) : 3440 (OH), 1735 cm⁻¹ (C(═O)OCH₂);

¹ H NMR (CDCl₃) δ : 2.50 (d, 2H, C-2 or C-4 CH₂, J=6.2), 2.63 (d, 2H,C-2 or C-4 CH₂, J=5.9), 3.33 (s, 1H, OH), 3.50 (s, 3H, NCH₃), 4.42 (m,1H, CHOH), 5.09 (s, 2H, --OCH₂), 5.80 (d, 1H, C-5 olefinic H, J=16),6.85-7.34 (m, 13H, ArH), 7.52 (d, 1H, C-7 olefinic H, J=16).

EXAMPLE 19 Sodium(±)-9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-5-oxo-6,8-nonadienoate

Phenylmethyl9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-5-oxo-6,8-nonadienoate(0.34g, 0.62 mmole) was dissolved in tetrahydrofuran (4mL) and water(1mL). 1N Sodium hydroxide (0.62 mL, 0.62 mmole) was added, and thesolution was stirred for 6 hours at 24° C. The mixture was diluted withwater (10 mL) and washed with diethyl ether (3×50 mL). The aqueousportion was lyophilized to give 0.17 g (52%) of the title compound;m.p.=166°-180° C. (dec.).

IR (KBr) ν_(max) : 1585 cm⁻¹ (COO⁻);

¹ H NMR (DMSO-d₆) δ : 1.76 (dd, 1H, C-4 CH, J=8.4,16), 1.97 (dd, 1H, C-4CH, J=3.5,16), 2.42 (m, 1H, C-2 CH₂), 3.71 (s, 3H, NCH₃), 3.93 (m, 1H,CHOC), 5.80 (d, 1H, C-6 olefinic H, J=16), 6.89-6.94 (m, 2H, ArH),7.06-7.12 (m, 2H, ArH), 7.30 (d, 1H, C-7 olefinic H, J=16), 7.38-7.41(m, 4H, ArH).

Anal. Calcd. for C₂₃ H₁₉ F₂ N₄ O₄ Na 3.5H₂ O: C, 51.21; H, 4.86; N,10.39. Found: C, 51.44; H, 3.97; N, 9.46.

EXAMPLE 20 Ethyl3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl)]-2-propenoateand ethyl3,3-bis(4-fluorophenyl)-2-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2-propenoatA. Ethyl 3,3-bis(4-fluorophenyl)-2-[2-(1-methylethyl)2H-tetrazol-5-yl]-2-propenoate

To a chilled (-78° C., dry ice-acetone) solution of ethyl3,3-bis(4-fluorophenyl)-2-(1-H-tetrazol-5-yl)-2-propenoate (2.6 g, 7.3mmoles) [prepared in Example 2] in 20 mL of dried N,N-dimethylformamideunder argon was added NaH (0.44 g, 11.0 mmoles; 60% in mineral oil)followed by reagent grade 2-iodopropane (2.0 mL, 20.0 mmoles) in onesingle portion. The thick reaction mixture was stirred under argon at-78° C. for 30 minutes and the mixture was allowed to warm to roomtemperature slowly over a period of 16 hours. Analytical TLC eluted oncewith 50% ethyl acetate in hexanes showed only one spot at R_(f) =0.86.The white suspension was diluted with 40 mL of half saturated brinefollowed by 20 mL of ethyl acetate. The aqueous layer was washed withethyl acetate (2×20 mL). The organic layers were combined, dried overMgSO₄ and concentrated under reduced pressure. Analytical TLC elutedfour times with 8% (v/v) ethyl acetate in hexanes showed two spots atR_(f) =0.38(21) and R_(f) =0.49 (21a). The desired products werepurified by silica gel column chromatography eluted with 8% EtOAc inhexanes. The fast moving product was collected to give 1.64 g (56.5%) ofthe title compound. MS (CI): m/e=399 for (M+H)⁺ ;

¹ H NMR(CDCl₃) δ : 7.29-6.85 (8H, m), 4.94 (1H, heptet, J=6.7 Hz), 4.09(2H, q, J=6.9 Hz), 1.50 (6H, d, J=6.8 Hz), 1.01 (3H, t, J=6.9 Hz);

¹³ C NMR (CDCl₃) δ : 167.04, 163.20 (d, ¹ J_(C-F) =284.4 Hz), 162.82 (d,¹ J_(C-F) =240 Hz), 152.65, 136.85, 136.19, 131.83 (d, ³ J_(C-F) =8.3Hz), 131.04 (d, ³ J_(C-F) =8.3 Hz), 115.97, 115.85, 115.34 (d, ² J_(C-F)=21.9 Hz), 115.11 (d, ² J_(C-F) =21.9 Hz), 61.38, 56.48, 22.04, 13.68ppm.

B. Ethyl3,3-bis(4-fluorophenyl-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoate

The silica gel column from the above Step A was eluted further with 8%EtOAc in hexanes to give the slower moving product (R_(f) =0.38). Theappropriate fractions were collected to give 0.95 g (32.7%) of the titlecompound. MS (CI): m/e=399 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ : 7.25-6.85 (8H, m), 4.30 (1H, heptet, J=6.8 Hz), 4.04(2H, q, J=7.1 Hz), 1.26 (6H, d, J=6.8 Hz), 1.01 (3H, t, J=7.1 Hz);

¹³ C NMR (CDCl₃) δ : 165.6, 162.7 (d, ¹ J_(C-F) =200 Hz), 155.7, 135.8,134.2, 132.1 (d, ³ J_(C-F) =8.3 Hz), 131.0 (d, ³ J_(C-F) =6.8 Hz), 115.8(d, ² J_(C-F) =21.9 Hz), 115.7 (d, ² J_(C-F) =21.9 Hz), 61.81, 51.07,22.18, 13.61 ppm.

EXAMPLE 213,3-Bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenalA.3,3-Bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoicacid

To a chilled (0° C.) solution of ethyl 3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoate (0.95g, 2.39 mmoles) in 20 mL of 1:1 (v/v) mixture of tetrahydrofuran andmethanol was added an aqueous solution of LiOH (4.0 mL, 3 Molar) in onesingle portion. The reaction mixture was stirred at 0° C. for 15 minutesfollowed by warming up to ambient temperature. Saponification wasallowed to proceed at room temperature for four hours forming a verypale clear solution. The crude reaction mixture was diluted with 12 mLof 2M H₂ SO₄ and the product was extracted into diethyl ether (40 mL×2).The organic layers were combined, dried over MgSO₄, concentrated underreduced pressure and then vigorously dried under high vacuum (0.01 mmHg)at room temperature for 24 hours to yield the title compound. Thepropenoic acid was then utilized in the next step without furtherpurification.

B.3,3-Bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenolchloride

A solution of the dried acid prepared in Step A in 20 mL of drymethylene chloride at room temperature was treated with 4 mL of oxalylchloride (redistilled over CaH₂). The mixture was refluxed under anargon atmosphere for two hours forming a light brownish solution. Mostof the volatile solvents were evaporated under reduced pressure and thelast traces of oxalyl chloride were removed under high vacuum (0.01mmHg) at room temperature for 12 hours to give the title compound.

C.3,3-Bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenol

The acid chloride prepared in Step B was dissolved in 20 ml of drytetrahydrofuran followed by the slow addition of 1.8 mL of lithiumaluminum hydride (1.0 Molar in tetrahydrofran) under an argon atmosphereat -78° C. Analytical TLC eluted once with 30% EtOAc in hexanes (v/v)showed the alcohol product at R_(f) =0.46. The crude reaction mixturewas poured into dilute H₂ SO₄ (2N in H₂ O) and the desired product wasextracted with three portions (40 mL×3)) of diethyl ether. The organicextracts were combined, dried over MgSO₄ and concentrated under reducedpressure to give 1.07 g of the title compound which was used withoutfurther purification in the next step.

D.3,3-Bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenal

The allylic alcohol (0.96 g) prepared in Step C was dissolved in 45 mLof dry methylene chloride at room temperature and to this vigorousystirred solution was added 0.64 g (2.96 mmoles) pyridinium chlorchromatein one single portion. After the reaction mixture was stirred for fourhours an analytical TLC eluted once with 10% EtOAc in hexanes (v/v) andtwice with 20% EtOAc in hexanes (v/v) showed one major product spot atR_(f) =0.22. The crude mixture was poured onto a bed of silica gel about1/2 inches thick and eluted with 20% EtOAc in hexanes to give 0.51 g(53%) of the title compound. MS (CI): m/e=355 for (M+H)⁺.

EXAMPLE 223,3-Bis(4-fluorophenyl)-2-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2-propenal

The general procedure of Example 21, Steps A, B, C, and D were repeated,except that the ethyl3,3-bis(4-flurophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoateutilized therein was replaced by ethyl3,3-bis(4-fluorophenyl)-2-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2-propenoateand there was thereby produced in 88% yield the title compound.

EXAMPLE 23 Ethyl9,9bis(4-fluorophenyl)-5-hydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8-nonadienoateand ethyl11,11-bis(4-fluorophenyl)-5-hydroxy-10-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8,10-undecatrienoateA.5,5-Bis(4-fluorophenyl)-4-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2,4-pentadienaland7,7-bis(4-fluorophenyl)-6-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2,4,6-heptatrienal

To a dry mixture of3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetazol-5-yl]-2-propenal(0.51 g, 1.4 mmoles) and triphenylphosphoranylidene acetaldehyde (0.48g, 1.6 mmoles) under argon at room temperature was added 24 mL drybenzene. The pale brownish suspension was vigorously stirred and heatedin an oil bath at about 120° C. The mixture was heated rapidly andreflux was continued overnight (ca. 16 hours). Analytical TLC of thebrownish solution eluted five times with 20% EtOAc in hexanes (v/v)showed only one spot at R_(f) =0.26; no traces of the starting aldehydewere detected. The crude reaction mixture was chromatographed on asilica gel column and eluted with about 1 liter of 25% EtOAc in hexanes(v/v). The appropriate fractions yielded 0.54 g (99%) of a mixture ofthe title compounds which was homogeneous by TLC. This material was usedin the next step without further purification.

B. Ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8nonadienoate and ethyl11,11-bis(4-fluorophenyl)-5-hydroxy-10-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8,10-undecatrienoate

Dianon of ethyl acetoacetate (0.36 mL, 2.8 mmoles) in tetrahydrofuran(2.5 mL) was generated as described in Example 10 using NaH (0.11 g, 2.8mmoles) (60% in mineral oil) and 2.5M n-BuLi in hexane (1.2 mL, 3.0mmoles) at 0° C. under argon. The dianion solution, after being chilledto -78° C., was transferred via a cannula into a tetrahydrofuran (5 mL)solution at -78° C. containing 0.52 g (1.4 mmoles) of dienal and trienalcompounds prepared in Step A. The reaction mixture was stirred at -78°C. under argon for 15 minutes. Analytical TLC eluted twice with 50%EtOAc in hexanes showed mostly one spot at R_(f) =0.41 along with aminor component at R_(f) =0.47. The pale brownish reaction mixture wasdiluted with 5 mL of 2M H₂ SO₄ and extacted with EtOAc (40 mL×2). Theorganic layers were combined, dried over MgSO₄ and concentrated underreduced pressure. The products were purified and isolated by silica gelcolumn chromatography using 20% EtOAc in hexanes (v/v) as the elutingsolvent. The appropriate fractions with R_(f) =0.41 were combined andevaporated to give 0.29 g (41%) of the title compound ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8-nonadienoate.¹ H NMR (CDCl₃) δ : 7.29-7.25 (2H, m), 7.12 (2H, t, J=8.64 Hz),6.93-6.81 (4H, m), 6.75 (1H, d, J=15.5 Hz), 5.27 (1H, dd, J=5.64, 15.5Hz), 4.62 (1H br.q, J=5.7 Hz), 4.29 (1H, heptet, J=6.6 Hz), 4.17 (2H, q,J=9.1 Hz), 3.46 (2H, br.s), 2.72 (2H, d, J=6.0 Hz), 1.26 (3H, t, J=9.1Hz), 1.3-1.2 (6H, br. hump) ppm.

The appropriate fracions with R_(f) =0.47 were combined and evaporatedto give 0.13 G (17.3%) of the title compound ethyl11,11-bis(4-fluorophenyl)-5-hydroxy-10-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8,10-undecatrienoate.

¹ H NMR (CDCl₃) δ : 7.29-7.22 (2H, m), 7.20-7.10 (2H, m), 6.91-6.80 (4H,m), 6.59 (1H, d, J=15.4 Hz), 6.29 (1H, dd, J=10.7, 15.2 Hz), 5.70 (1H,dd, J=10.7, 15.4 Hz), 5.84 (1H, dd, J=9.9, 15.5 Hz), 4.62 (2H, br), 4.27(1H, heptet, J=6.6 Hz), 4.17 (2H, q, J=7.0 Hz), 3.46 (2H, s), 3.1 (1H,br, D₂ O exchangeable), 2.75-2.69 (2H, m), 1.26 (3H, t, J=7.0 Hz),1.38-1.05 (6H, br. humps, hindered rotation on isopropyl group) ppm.

EXAMPLE 24 Ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6,8-nonadienoateand Ethyl7,7-bis(4-fluorophenyl)-5-hydroxy-6-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6-heptenoate

The general procedure of Example 23, Step A was repeated, except thatthe3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenalutilized therein was replaced by3,3-bis(4-fluorophenyl)-2-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2-propenaland there was thereby produced mostly5,5-bis(4-fluorophenyl)-4-[2-(1-methylethy)-2H-tetrazol-5-yl]-2,4-pentadienalin 82% yield; MS (CI): m/e=381 for (M+H)⁺. This product was thensubjected to the general procedure of Example 23, Step B and there wasthereby produced ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6,8-nonadienoatecontaining some inseparable rthyl7,7-bis(4-fluorophenyl)-5-hydroxy-6-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6heptenoatein 69% yield.

¹ H NMR (CDCl₃) δ : 7.31-7.11 (2H, m), 7.10-7.04 (2H, m), 6.91-6.78 (4H,m), 6.72 (1H, d, J=15.5 Hz), 5.46 (1H, dd, J=5.91, 15.7 Hz), 4.95 (1H,heptet J=6.8 Hz), 4.64 (1H, br.S), 4.17 (2H, q, J=7.2 Hz), 3.46 (2H, s),2.75-2.72 (2H, m), 1.49 (6H, d, J=6.8 Hz), 1.28 (3H, t, J=7.2 Hz) ppm.

EXAMPLE 25 Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl)-6,8-nonadienoate

A solution of ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8-nonadienoate0.29 g (0.57 mmole) in 6 mL of dry tetrahydrofuran at 0° C. (ice-waterbath) under argon, was treated with 0.65 mL of triethylborane intetrahydrofuran (1.0 Molar solution). The reaction mixture was stirredat -5° C. to 0° C. for an hour before it was chilled to -78° C. (dryice-acetone bath) under argon. To this pale yellow solution was addedsolid NaBH₄ (25 mg, 0.66 mmole) and the reduction was allowed to proceedat -78° C. for a period of two hours. The reduction was accelerated byadding 25 μL of absolute CH₃ OH. After an additional hour, analyticalTLC eluted once with 1:1 (v/v) EtOAc in hexanes showed completedisappearance of the starting material. The cold reaction mixture wasdiluted with 20 mL 1M H.sub. 2 SO₄ and organic material was extractedinto EtOAc (40 mL×2). The organic layers were combined, dried over MgSO₄and concentrated under reduced pressure to give a pale yellow syrup. Thesyrup was redissolved in 200 mL of MeOH and the solution was allowed tostand at room temperature overnight. Analytical TLC eluted twice with50% EtOAc in hexanes showed mostly one major spot at R_(f) =0.32.Purification by silica gel column chromatography using 30% (v/v) EtOAcin hexanes yielded 0.23 g (79%) of the title compound.

IR (KBr) ν_(max) : 3438 (v.br), 1731 (s), 1600 (s), 1503 (s), 1225 (s),1156 (s), 838 (s), 750 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 7.29-7.25 (2H, m), 7.12 (2H, t, J=8.6 Hz), 6.61-6.93(4H, m), 6.73 (1H, d, J=15.8 Hz), 5.25 (1H, dd, J=15.8, 6.5 Hz), 4.42(1H, q, J=5Hz), 4.30 (1H, heptet, J=6.7 Hz), 4.22 (1H, m), 4.22 (2H,v.br. D₂ O exchangeable), 4.16 (2H, q, J=7.2 Hz), 2.47-2.45 (2H, m),1.59-1.57 (2H, m), 1.26 (3H, t, J=7.2 Hz), 1.4-1.0 (6H, br, hinderedrotation on the isopropyl group;

¹³ C NMR (CDCl₃) δ : 172.26, 162.8 (d, ¹ J_(C-F) =250.7 Hz), 162.41 (d,¹ J_(C-F) =250.7 Hz), 152.10, 146.19, 138.44, 137.88, 135.98, 135.40,132.32 (d, ³ J_(C-F) =8.3 Hz), 131.72 (d ³ J_(C-F) =8.3 Hz), 127.61,121.81, 115.71, (d, ² J_(C-F) =21.1 Hz), 115.48 (d, ² J_(C-F) =21.1 Hz),71.63, 68.20, 60.77, 50.78, 42.29, 41.68, 24-20 (v.br for isopropylsignal due to restricted rotation), 14.14 ppm;

Anal. Calcd. for C₂₇ H₃₀ F₂ N₄ O₄ : C, 59.11; H, 6.25; N, 10.21. Found:C, 60.40; H, 5.66; N, 9.91.

EXAMPLE 26 Ethyl(±)-erythro-11,11-bis(4-fluorophenyl)-3,5-dihydroxy-10-[1-(1-methylethyl)-1H-tetrazol-5-yl]-6,8,10-undecatrienoate

The general procedure of Example 25 was repeated, except that the ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8-nonadienoateutilized therein was replaced by ethyl 11,11-bis(4-fluorophenyl)-5-hydroxy-10-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8,10-undecatrienoate(0.13 g, 0.24 mmole) and there was thereby produced 140 mg of the titlecompound.

¹ H NMR (CDCl₃) δ : 7.29-7.22 (2H, m), 7.13 (2H, t, J=8.6 Hz, 6.92-6.80(4H, m), 6.58 (1H, d, J=15.4 Hz), 6.27 (1H, dd, J=10.7, 15.1 Hz), 5.70(1H, dd, J=10.6, 15.5 Hz), 5.66 (1H, dd, J=5.8, 15.4 Hz), 4.43 (1H, q,J=6.0 Hz), 4.27 (1H, heptet, J=6.5 Hz), 4.24 (1H, m), 4.15 (2H, q, J=7.2Hz), 3.91 (1H, br, D₂ O exchangeable) 3.78 (1H, br, D₂ O exchangeable),2.48-2.43 (2H, m), 1.65-1.58 (2H, m), 1.42-1.32 and 0.97-0.67 (v.br.humps for isopropyl signals), 1.26 (3H, , J=7.2 Hz) ppm.

EXAMPLE 27 Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(1-methylethyl)-2H-tetrazol-5-yl}-6,8-nonadienoateand ethyl(±)-erythro-7,7-bis(4-fluorophenyl)-3,5-dihydroxy-6-[2-(1-mehylethyl)-2H-tetrazol-5-yl]-6-heptenoate

The general procedure of Example 25 was repeated, except that the ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-3-oxo-6,8-nonadienoateutilized therein was replaced by ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6,8-nonadienoatecontaining some ethyl7,7-bis(4-fluorophenyl)-5-hydroxy-6-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6-heptenoate[prepared in Example 24] and there was thereby produced after silica gelcolumn chromatography the title compounds in 53% and 38% yield,respectively.

¹ H NMR (CDCl₃) δ: 7.28-7.23 (2H, m), 7.07 (2H, t, J=8.6 Hz), 6.86-6.71(4H, m), 6.66 (1H, d, J=15.7 Hz), 5.45 (1H, dd, J=6.4, 15.8 Hz), 4.95(1H, heptet, J=6.7 Hz), 4.43 (1H, br), 4.22 (1H, br), 4.16 (2H, q, J=7.2Hz), 3.90 (1H, br, D₂ O exchangeable), 3.64 (1H, br. D₂ O exchangeable),2.47-2.43 (2H, m), 1.67-1.60 (2H, m), 1.48 (6H, d, J=6.7 Hz), 1.25 (3H,t, J=7.2 Hz);

¹³ C NMR (CDCl₃) δ : 172.32, 163.77, 162.53 (d, ¹ J_(C-F) =248.4 Hz),161.86 (d, ¹ J_(C-F) =247.6 Hz), 145.61, 137.88, 137.05, 136.28, 132.38(d, ¹ J_(C-F) =8.3 Hz), 131.64 (d, ³ J_(C-F) =8.3 Hz), 131.19, 131.08,128.36, 125.42, 115.58 (d, ² J_(C-F) =21.9 Hz), 114.67 (d, ² J_(C-F)=21.9 Hz), 72.15, 68.08, 60.74, 56.41, 42.54, 41.73, 22.04, 14.17 ppmand

¹ H NMR (CDCl₃) δ : 7.30-7.26 (2H, m), 7.07 (2H, t, J=8.6 Hz), 6.94-6.70(2H, m), 6.83-6.77 (2H, m), 4.92 (1H, heptet, J=6.7 Hz), 4.24 (1H, m),4.92 (1H, m, methine proton adjacent to one of the hydroxy groups), 4.14(2H, q, J=7.1 Hz), 4.00 (1H, d, J=6.5 Hz, D₂ O exchangeable), 3.54 (1H,d, J=2.5 Hz), 2.45-2.42 (2H, m), 1.85 (2H, t, J=6.1 Hz), 1.48 (3H, d,J=6.8 Hz), 1.47 (3H, d, J=6.8 Hz), 1.25 (3H, t, J=7.1 Hz),

¹³ C NMR (CDCl₃) δ : 172.18, 162.91, 162.51, (d, ¹ J_(C-F) =248.4 Hz),162.00 (d, ¹ J_(C-F) =246.9 Hz), 146.44, 137.33, 135.98, 131.26 (d, ³J_(C-F) =8.3 Hz), 131.19 (d, ¹ J_(C-F) =8.3 Hz), 128.33, 115.52 (d, ²J_(C-F) =21.1 Hz), 114.73 (d, ² J_(C-F) =21.9 Hz), 71.31, 67.77, 60.65,56.50, 41.85, 41.45, 21.98, 14.18 ppm, respectively.

EXAMPLE 28 Sodium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-6,8-nonadienoate

To a solution of ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-6,8-nonadienoate(230 mg, 0.45 mmole) in 10 mL of tetrahydrofuran at 0° C. (ice-waterbath) was added 450 L (1.0 equivalent) of 1N NaOH solution. The emulsionwas stirred at 0° C. for one hour forming a clear homogeneous solution.Analytical TLC eluted twice with 50% EtOAc in hexanes showed only oneimmobile spot at the origin. Most of the volatile solvents were removedunder reduced pressure at 10°-15° C. and the aqueous solution waslyophilized under high vacuum at 0° C. to give the title compound inquantitative yield; m.p.>120° C. decomposed.

IR (KBr) ν_(max) : 3438 (v.br), 1600 (s), 1581 (s), 1513 (s), 1400 (s),1225 (s), 1160 (s), 838 (s) cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.41-7.29 (4H, m), 7.07-6.91 (4H, m), 6.53 (1H, d,J=15.6 Hz), 5.06 (1H, dd, J=5.4, 15.7 Hz), 4.48 (1H, heptet, J=6.6 Hz),4.14 (1H, q, J=5.9 Hz), 3.64 (1H, m), 3.8-3.2 (2H br. humps), 2.02 (1H,dd, J=3.6, 15.0 Hz), 1.84 (1H, dd, J=8.4, 14.9 Hz), 1.5-1.3 (1H, m),1.3-1.1 (1H, m), 1.15 (6H, br.s, isopropyl signals showed restrictedrotation);

¹³ C NMR (DMSO-d₆) δ : 176.30, 161.82 (d, ¹ J_(C-F) =246.1 Hz), 161.41(d, ¹ J_(C-F) =246.9 Hz), 151.53, 144.45, 139.87, 136.11, 135.45, 132.14(d, ³ J_(C-F) =8.3 Hz), 131.28 (d, ³ J_(C-F) =8.3 Hz), 125.39, 122.23,115.44 (d, ² J_(C-F) =21.9 Hz), 115.05 (d, ² J_(C-F) =21.9 Hz), 68.14,65.68, 50.05, 44.48, 43.48, 22.06 ppm;

Anal. Calcd. for C₂₅ H₂₅ F₂ N₄ O₄ Na 2H₂ O: C, 55.35; H, 5.39; N, 10.32.Found: C, 54.63; H, 4.79; N, 9.35.

EXAMPLE 29 Sodium(±)-erythro-11,11-bis(4-fluorophenyl)-3,5-dihydroxy-10-[1-(1-methylethyl)-1H-tetrazol-5-yl]-6,8,10-undecatrienoate

The product of Example 26 was subjected to the general procedure ofExample 28 and there was thereby produced the title compound inquantitative yield; m.p.>100° C. decomposed.

IR (KBr) ν_(max) : 3425 (v.br), 1600 (s), 1575 (sh, s), 1513 (s), 1400(s), 1225 (s), 1163 (s), 838 (s) cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.42-7.30 (4H, m), 7.14-7.03 (2H, m), 6.92-6.87(2H, m), 6.46 (1H, d, J=15.4 Hz), 6.17 (1H, dd, J=14.8, 15.4 Hz), 5.72(1H, dd, J=5.2, 14.9 Hz), 5.61 (1H, dd, J=10.9, 15.3 Hz), 5.0 (1H, br),4.48 (1H, heptet, J=6.6 Hz), 4.12 (1H, m), 3.64 (1H, br), 2.01 (1H, d,J=12.6 Hz), 1.84 (1H, dd, J=8.0, 14.3 Hz), 1.6-0.8 (6H, v.br. hump,isopropyl signals showed restricted rotation);

¹³ C NMR (DMSO-d₆) δ : 175.93, 162 (d, ¹ J_(C-F) 250 Hz), 161 (d, ¹J_(C-F) 250 Hz), 151.35, 144.71, 141.56, 136.09, 135.57, 133.82, 132.31(d, ³ J_(C-F) =8.3 Hz), 131.41 (d, ³ J_(C-F) =8.3 Hz), 128.65, 127.61,122.58, 115.46 (d, ² J_(C-F) =21.1 Hz), 115.14 (d, ² J_(C-F) =21.9 Hz),68.41, 65.83, 50.11, 44.65, 43.51, 22.07 (v.br signals for isopropylcarbon) ppm.

EXAMPLE 30 Sodium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(1-methylethyl)-2H-tetrazol-5-yl]-6,8-nonadienoate

The ethyl9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(1-methylethyl)-2H-tetrazol-5-yl]-6,8nonadienoateprepared in Example 27 was treated by the general procedure of Example28 and there was thereby produced the title compound a in quantitativeyield; m.p.>120° C. decomposed.

IR (KBr) ν_(max) : 3438 (v.br), 1600 (s), 1513 (s), 1483 (m), 1400 (m),1321 (s), 1225 (s), 1188 (m), 1156 (s), 838 (S) cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.29-7.22 (4H, m), 6.95 (2H, t, J=8.8 Hz),6.84-6.78 (2H, m), 6.53 (1H, d, J=15.6 Hz), 5.34 (1H, dd, J=5.6, 15.6Hz), 5.02 (1H, heptet, J=6.7 Hz), 4.15 (1H, q, J=5.9 Hz), 3.65 (1H, q,J=4.0 Hz), 3.37 (2H, br.S, D₂ O exchangeable), 2.04 (1H, dd, J=15.0, 3.5Hz), 1.85 (1H, dd, J=8.6, 15.1 Hz), 1.40 (6H, d, J=6.7 Hz), 1.47-1.23(2H, br. humps);

¹³ C NMR (DMSO-d₆) δ : 176.28, 162.88, 161.59 (d, ¹ J_(C-F) =246.13 Hz),160.94 (d, ¹ J_(C-F) =245.4 Hz), 143.20, 139.49, 137.81, 136.26, 132.06(d, ³ J_(C-F) =8.3 Hz), 131.30 (d, ³ J_(C-F) =8.3 Hz), 130.93, 126.00,125.85, 115.32 (d, ² J_(C-F) =21.9 Hz), 114.46 (d, ² J_(C-F) =21.9 Hz),79.09, 68.53, 65.83, 55.72, 44.64, 43.53, 30.36, 21.69 ppm.

Anal. Calcd. for C₂₅ H₂₅ F₂ N₄ O₄ Na 2H₂ O: C, 55.35; H, 5.39; N, 10.32;Found: C, 55.96; H, 4.86; N, 10.27.

EXAMPLE 31 Sodium(±)-erythro-7,7-bis(4-fluorophenyl)-3,5-dihydroxy-6-[2-(1-methylethyl)-2H-tetrazol-5-yl]-6-heptenoate

The ethyl7,7-bis(4-fluorophenyl)-3,5-dihydroxy-6-[2-(1-methylethyl)-2H-tetrazol-5-yl]-6-heptenoateprepared in Example 27 was treated by the general procedure of Example28 and there was thereby produced the title compound in quantitativeyield; m.p.>120° C. decomposed.

IR (KBr) ν_(max) : 3438 (s, v.br), 1600 (s), 1575 (s), 1512 (s), 1406(s), 1225 (s), 1156 (s), 838 (s) cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.41-7.36 (2H, m), 7.23 (2H, t, J=8.7 Hz), 6.93(2H, t, J=8.8 Hz), 6.86-6.82 (2H, m), 4.98 (1H, heptet, J=6.7 Hz), 4.67(1H, t, J=6.7 Hz), 3.76 (1H, m), 3.35 (br.S, D₂ O exchangeable), 1.99(1H, dd, J=3, 15.0 Hz), 1.80-1.63 (3H, m), 1.41 (3H, d, J=6.4 Hz), 1.38(3H, d, J=6.5 Hz);

¹³ C NMR (DMSO-d₆) δ : 176.42, 161.34 (d, ¹ J_(C-F) =244.6 Hz), 160.7(d, ¹ J_(C-F) =237.1 Hz), 162.25, 143.93, 137.88, 136.44, 131.11 (d, ³J_(C-F) =8.0 Hz), 130.85 (d, ³ J_(C-F) =8.0 Hz), 114.97 (d, ² J_(C-F)=21.1 Hz), 114.33 (d, ² J_(C-F) =21.1 Hz) 67.76, 65.80, 55.40, 43.12,42.89, 30,33, 21.78, 21.58 ppm (nonequivalent isopropyl signals);

Anal. Calcd. for C₂₃ H₂₃ F₂ N₄ O₄ Na H₂ O: C, 55.42; H, 5.05; N, 11.24;Found: C, 56.01; H, 4.94; N, 10.79.

EXAMPLE 32 Ethyl3,3-bis(4-fluorophenyl)-2-[2-(1,1-dimethyl-ethyl)-2H-tetrazol-5-yl]-2-propenoate

To a stired suspension of 10 mg of 10 g of ethyl3,3-bis-(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate in 250 mL drydiethyl ether cooled at -50° C. was slowly added 60 mL of liquidisobutylene (previously condensed from gaseous material in a dryice-alcohol bath). With continued stirring and cooling, 50 mL ofconcentrated H₂ SO₄ was added slowly and carefully. The mixture was thensealed in a stainless steel Parr container and stirred at -30° C. for 40hours. After releasing the pressure, the mixture was added slowly andcarefully to excess saturated NaHCO₃ solution. The aqueous mixture wasextracted with diethyl ether, dried over Na₂ SO₄ and concentrated invacuo to give 7.8 g (67.8%) of the title compound, m.p. 143-144° C.

IR (KBr) ν_(max) : 3438 (v.br.), 1738 (s), 1625 (s), 1600 (s), 1240 (s),1225 (s), 842 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 7.29-7.24 (2H, m), 7.07-6.84 (6H, m), 4.10 (2H, q),1.59 (9H, s), 1.03 (3H, t) ppm.

Anal. Calcd. for C₂₁ H₂₂ F₄ N₄ O₂ : C, 64.07; H, 5.38; N, 13.58. Found:C, 64.15; H, 5.25, N, 13.58.

Example 33 3,3-Bis(4-fluorophenyl)-2-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-2-propenalA.3,3-Bis(4-fluorophenyl)-2-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-2-propenol

To a stired solution of ethyl3,3-bis(4-fluorophenyl)-2-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-2-propenoate(2.0 g, 4.8 mmoles) in dry methylene chloride (10 mL) under argon at-78° C. was added 10 mL of diisobutylaluminum hydride solution (1.0Molar solution in methylene chloride) over a period of three minues. Thereduction was llowed to proceed at -78° C. under argon for two hours.Analytical TLC eluted twice with 20% (v/v) ethyl acetate in hexanesshowed no starting material at R_(f) =0.42 and a major spot at R_(f)=0.14 for desired product. The crude reaction misture (at -78° C.) wasdiluted with 10 mL of 2N HCl followed by extractions with ethyl acetate(40 mL×2). The organic layers were combined, dried over MgSO₄,evaporated under reduced pressure and dried under high vacuum at roomtemperature overnight to give the title compound which was used withoutfurther purification in the next step.

¹ H NMR (60 MHz) (CDCl₃) δ : 7.4-6.9 (8H, m), 9.7 (≃1/4H, s, smallamount of aldehyde), 4.6 (2H, d, J=6 Hz), 1.56 (9H, s) ppm.

B.3,3-Bis(4-fluorophenyl)-2-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-2-propenal

The crude allylic alcohol prepared in Step A was dissolved in 60 mL ofdry methylene chloride and to this vigorously stirred solution at roomtemperature under argon was added pyridinium chlorochromate (1.2 g, 5.5mmoles) in one single portion. The slightly exothermic oxidation wasallowed to proceed at room temperature for two hours. Analytical TLCeluted twice with 20% (v/v) ethyl acetate in hexanes showed the aldehydeat R_(f) =0.35. The crude reaction mixture was chromatographed on asilica gel column and eluted with 1 liter of 5% (v/v) ethyl acetate inhexanes to give 1.59 g (89%) of a TLC homogenous product.Recrystallization from EtOAc-hexanes mixture yielded pure titlecompound; m.p. 131°-133° C.

IR (KBr) ν_(max) : 3488 (m), 1669 (s), 1600 (s), 1508 (s), 1475 (m),1231 (s), 1219 (s), 1156 (s), 850 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 9.72 (1H, s), 7.38-7.33 (2H, m), 7.17 (2H, t, J=8.6Hz), 7.00-6.84 (4H, m), 1.63 (9H, s);

¹³ C NMR (CDCl₃) δ : 190.14, 164.27 (d, ¹ J_(C-F) =246.1 Hz), 163.35 (d,¹ J_(C-F) =240 Hz), 162.5, 160.9, 135.82, 133.58, (d, ³ J_(C-F) =8.3Hz), 132.26 (d, ³ J_(C-F) =8.3 Hz), 128.4, 115.85 (d, ² J_(C-F) =21.9Hz), 115.22 (d, ² J_(C-F) =21.9 Hz), 63.95, 29.24 ppm;

Anal. Calcd. for C₂₀ H₁₈ F₂ N₄ O: C, 65.21; H, 4.92; N, 15.21. Found: C,65.33; H, 4.93; N, 15.44.

EXAMPLE 345,5-Bis(4-fluorophenyl)-4-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-2,4-pentadienal

To a warm, stirring solution of3,3-bis(4-fluorophenyl)-2-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]2-propenal(1.59 g, 4.3 mmoles) in 60 mL of dry benzene under argon was addedtriphenylphosphoranylidene acetaldehyde (1.45 g, 4.7 mmoles) in onesingle portion. The reagents dissolved rapidly into the warm (55° C.)solution and the homogeneous mixture was gradually heated to reflux for16 hours. Analytical TLC eluted five times with 20% (v/v) ethyl acetatein hexanes showed the desired product at R_(f) =0.52. The crude reactionmixture was chromatographed on a silica gel column and eluted with 10%(v/v) ethyl acetate in hexanes to give 1.7 g of product.Recrystallization from EtOAc-hexanes mixture yielded pure titlecompound; m.p.=171°-174° C.

IR (KBr) ν_(max) : 3000 (s), 1675 (s), 1669 (s), 1600 (s), 1508 (s),1225 (s), 1159 (s), 1119 (s), 843 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 9.55 (1H, d, J=7.4 Hz), 7.50 (1H, d, J=15.6 Hz),7.33-7.26 (2H, m), 7.18-7.13 (2H, m), 6.92-6.79 (4H, m), 5.96 (1H, dd,J=7.5, 15.6 Hz), 1.63 (9H, s);

¹³ C NMR (CDCl₃) δ : 193.38, 163.5 (d, ¹ J_(C-F) =240 Hz), 162.5 (d, ¹J_(C-F) =240 Hz), 154.5, 151.5, 149.49, 137.0, 135.5, 132.81 (d, ³J_(C-F) =8.3 Hz), 132.05 (d, ³ J_(C-F) =8 Hz), 115.80 (d, ² J_(C-F)=21.9 Hz), 114.98 (d, ² J_(C-F) =21.9 Hz), 64.3, 29.23 ppm;

Anal. Calcd. for C₂₂ H₂₀ F₂ N₄ O: C, 66.99; H, 5.10;N, 14.18. Found: C,67.14; H, 5.17; N, 14.55.

EXAMPLE 35 Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(1,1-dimethylethyl)-2H-terazol-5-yl)-6,8-nonadienoate.A. Ethyl9,9bis(4-fluorophenyl)-5-hydroxy-8-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate

A solution of the dianion of ethyl acetoacetate (400 μL, 3.1 mmoles) in8 mL of dry tetrahydrofuran was generated as described in Example 10using 130 mg (3.2 mmoles) of NaH (60% in mineral oil) and 2.5M n-BuLi inhexanes (1.27 mL, 3.2 mmoles) at 0° C. under argon. The orange dianionsolution, after being chilled to -78° C., was transferred via a cannulainto a tetrahydrofuran (12 mL) solution at -78° C. containing5,5-bis(4-fluorophenyl)-4-[2-(1,1-dimethylethyl)-2H-tetazol-5-yl]-2,4-pentadienal(0.96 g, 2.4 mmoles). The reaction mixture was stirred at -78° C. forfive minutes. Analytical TLC eluted once with 50% (v/v) EtOAc in hexanesshowed the major product spot at R_(f) =0.35. The reaction mixture wasdiluted with 20 mL of 1N HCl and the organic material was extracted withEtOAc (20 mL×2). The organic layers were combined, dried over MgSO₄,evaporated under reduced pressure, and dried under high vacuum (0.001mmHg) at ambient temperature overnight (16 hours) to give the titlecompound which was used in the next step without further purification.

B. Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(1,1-dimethylethyl)-2H-tetazol-5-yl)-6,8-nonadienoate

The crude ketone from Step A was dissolved in 10 mL of drytetrahydrofuran under argon at 0° C. To this pale brownish solution wasadded 3.0 mL of 1.0 Molar triethylborane in tetrahydrofuran. The mixturewas allowed to stir at 0° C. for 1.5 hours before it was chilled to -78°C. (dry ice-acetone bath). To this stirring solution was added 120 mg(3.2 mmoles) of NaBH₄ and the reduction was allowed to proceed at -78°C. for a period of three hours. The cold reaction mixture was dilutedwith 10 mL of 1N HCl and the product was extracted into ethyl acetate(40 mL×2). The organic layers were combined, dried over MgSO₄ andevaporated to dryness. The crude product was redissolved into 200 mL ofabsolute methanol and the solution was stirred for 16 hours. AnalyticalTLC eluted with 50% (v/v) ethyl acetate in hexanes showed only one majorspot at R_(f) =0.31. Silica gel column chromatography using 10-20% EtOAcin hexanes as the eluting solvent yielded 1.07 g (83.5%) of the titlecompound.

IR (KBr) ν_(max) : 3438 (s), 1731 (s), 1600 (s), 1503 (v.s.), 1225 (s),1156 (s), 838 (s), 750 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ : 7.28-7.24 (2H, m), 7.07 (2H, t, J=8.6 Hz), 6.86-6.73(4H, m), 6.69 (1H, d, J=15.7 Hz), 5.48 (1H, dd, J=6.3, 15.8 Hz), 4.44(1H, m), 4.23 (1H, m), 4.16 (2H, q, J=7.0 Hz), 3.85 (1H, br, D₂ Oexchangeable), 3.50 (1H, br. D₂ O exchangeable), 2.48-2.45 (2H, m),1.69-1.54 (2H, m), 1.59 (9H, s), 1.26 (3H, t, J=7.0 Hz);

¹³ C NMR (CDCl₃) δ : 172.38, 162.5 (d, ¹ J_(C-F) =249.2 Hz), 161.82 (d,¹ J_(C-F) =2.48.4 Hz), 145.53, 137.96, 136.96, 136.29, 132.35 (d, ³J_(C-F) =8.3 Hz), 131.61 (d, ³ J_(C-F) =7.6 Hz), 128.39, 125.58, 115.31(d, ² J_(C-F) =21.9 Hz), 114.59 (d, ² J_(C-F) =21.9 Hz), 72.24, 68.10,63.75, 60.75, 42.52, 41.62, 29.16, 14.15 ppm.

Anal. Calcd. for C₂₈ H₃₂ F₂ N₄ O₄ H₂ O: C, 61.75; H, 6.29; N, 10.28.Found: C, 61.22; H, 6.03; N, 10.02.

EXAMPLE 36 Sodium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(1,1-dimethylethyl-2H-tetrazol-5-yl)-6,8-nonadienoicacid, sodium salt

To a solution of ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl-6,8-nonadienoate(330 mg, 0.63 mmole) in 6 mL of tetrahydrofuran at 0° C. was added 630μL of 1 Molar NaOH solution. The turbid suspension was stirred at 0° C.for 30 minutes and then at ambient temperature for an additional 2.5hours forming a clear homogeneous solution. Analytical TLC eluted oncewith 50% (v/v) ethyl acetate in hexanes showed no starting materialother than the immobil spot at the origin. Most of the volatile solventswere evaporated under reduced pressure at about 10°-15° C. The solutionof the sodium salt of the product was lyophilized under high vacuum togive 320 mg (quantitative) of the title compound; m.p. >120° C.decomposed.

IR (KBr) ν_(max) : 3413 (v.br), 1600 (s), 1575 (s), 1503 (s), 1338 (s),1225 (s), 1156 (s), 838 (s) cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ: 7.29 (4H, d, J=7.2 Hz), 6.95 (2H, t, J=8.9 Hz),6.83-6.78 (2H, m), 6.53 (1H, d, J=15.5 Hz), 5.37 (1H, dd, J=5.6, 15.6Hz), 5.0 (1H, br. D₂ O exchangeable), 4.16 (1H, q, J=6.1 Hz), 3.67 (1H,m), 3.37 (1H, br. D₂ O exchangeable, 2.05 (1H, dd, J=15.1, 3.5 Hz), 1.86(1H, dd, J=8.6, 15.1 Hz), 1.53-1.29 (2H, m), 1.54 (9H, s);

¹³ C NMR (DMSO-d₆) δ: 176.40, 162.50, 161.54 (d, ¹ J_(C-F) =246.1 Hz),160.98 (d, ¹ J_(C-F) =259.7 Hz), 143.15, 139.54, 137.87, 136.23, 132.0(d, ³ J_(C-F) =8.3 Hz), 131.25 (d, ³ J_(C-F) =7.6 Hz), 125.91, 115.31(d, ² J_(C-F) =21.9 Hz), 114.43 (d, ² J_(C-F) =21.9 Hz), 68.45, 65.75,63.35, 44.64, 43.52, 28.53 ppm.

Anal. Calcd. for C₂₆ H₂₇ F₂ N₄ O₄ Na H₂ O: C, 56.11; H, 5.61; N, 10.07.Found: C, 56.96; H, 5.06; N, 9.99.

EXAMPLE 37 4,4'-Difluoro-3,3'-dimethylbenzophenone

2-Fluorotoluene (8 ml, 73 mmoles) was added to a vigorously stirredmixture of aluminum chloride (61.43 g, 460 mmoles) and carbontetrachloride (135 ml) at 0° C. After 10 minutes 2-fluorotoluene (92 ml,837 mmoles) in carbon tetrachloride (75 mL) was added dropwise over 4hours and the mixture stirred for 2 hours at 0° C. WARNING: Aspontaneous vigorous reaction occurred after the addition of2-fluorotoluene. The mixture was cooled to -20° C. and quenched with 2NHCl (250 mL). The organic layer was separated, washed with brine anddried (MgSO₄). The solvent was removed by evaporation and the residuedissolved in benzene (200 mL) and treated with water (200 mL) and aceticacid (50 ml). After stirring for 15 hours, the organic layer wasseparated, dried (MgSO₄) and evaporated. Crystallization from ethanolafforded 50 g (49%) of the title compound; m.p.=128°-130° C.

IR (KBr) ν_(max) : 1650 cm⁻¹.

¹ H NMR (CDCl₃) δ: 7.66 (d, J=7.3 Hz, 2H), 7.58 (m, 2H), 7.09 (t, J=8.8Hz, 2H), 2.32 (s, 6H).

Anal. Calcd. for C₁₅ H₁₂ F₂ O: C, 73.16; H, 4.91. Found: C, 72.96; H,4.80.

EXAMPLE 381,1-Bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl) ethanol

A solution of 1,5-dimethyltetrazole (2.55 g, 26 mmoles) in drytetrahydrofuran (15 ml) at -78° C. was treated with n-butyllithium (12.5ml of a 2.5M solution in hexane, 31.2 mmoles) and the mixture stirredfor 15 minutes. 4,4'-Difluoro-3,3'-dimethylbenzophenone (5 g, 20.3mmoles) in dry tetrahydrofuran (20 ml) was added, the mixture stirredfor 1 hour, then quenched with 2N HCl (250 ml). The aqueous phase wasextracted with ethyl acetate (3×50 ml) and the combined organic layerwas dried (MgSO₄) and evaporated. The residue was purified by silica gelcolumn chromatography using 20% (v/v) EtOAc-hexane as eluent to afford3.7 g, (52%) of the product. Recrystallization from EtOAc-hexanesyielded the title compound; m.p. 41°-42° C.

IR (KBr) ν_(max) : 3400 (br) cm⁻¹ ;

¹ H NMR (CDCl₃) δ: 7.20 (d, J=7.1 Hz), 2M), 7.10 (m, 2H), 6.88 (t, J=8.6Hz, 2H), 4.84 (s, 1H), 3.77 (s, 3H), 3.71 (s, 2H), 2.20 (s, 6H);

Anal. Calcd. for C₁₈ H₁₈ F₂ N₄ O: C, 62.79; H, 5.27; N, 16.27. Found: C,62.73; H, 5.32; N, 16.16.

EXAMPLE 391,1-Bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of1,1-bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol(3.58 g, 10.9 mmoles) and potassium hydrogen sulfate (530 mg) was heatedat 195° C. for 1.5 hours. The mixture was cooled to 70° C. andchloroform (50 ml) was added. The insoluble material was removed byfiltration and the filtrate evaporated. The residue was crystallizedfrom EtOAc-Hexane to afford 3.38 g (100%) of the title compound;m.p.=138°-139° C.

¹ H NMR (CDCl₃) δ: 7.20-6.80 (m, 6H), 6.65 (s, 1H), 3.56 (s, 3H), 2.28(s, 3H), 2.18 (s, 3H).

Anal. Calcd. for C₁₈ H₁₆ F₂ N₄ : C, 66.25; H, 4.95; N, 17.17. Found: C,66.15; H, 5.05; N, 17.24.

EXAMPLE 403,3-Bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

A solution of1,1-bis(4-fluoro-3-methylphenyl)-2-(1-methyltetrazol-5-yl)ethene (3.58g, 11.0 mmoles)) in dry tetrahydrofuran (20 mL) at -78° C. was treatedwith n-butyllithium (5.3 ml of 2.5M solution in hexane; 13.25 mmoles)and the mixture stirred at -78° C. for 0.5 hours. Ethyl formate (1.33ml; 1.22 g, 16.5 mmoles) was added and the mixture was allowed to warmup to 23° C. over 1 hour, then quenched with 2N HCl (250 mL). Theaqueous phase was extracted with ethyl acetate (3×50 mL) and thecombined organic layers were dried (MgSO₄) and evaporated. The residuewas purified by chromatography using 20% EtOAc-Hexane as eluent toafford 2.2 g (57%) of the title compound as a foam. MS (CI): m/e=355 for(M+H)⁺ ;

IR (KBr) ν_(max) : 1660 cm⁻¹ ;

¹ H NMR (CHCl₃) δ: 9.62 (s, 1H), 7.25-7.05 (m, 3H), 6.85-6.65 (m, 3H),3.73 (s, 3H), 2.34 (s, 3H), 2.13 (s, 3H).

Anal. Calcd. for C₁₉ H₁₆ F₂ N₄ O: C, 64.41; H, 4.56; N, 15.82. Found: C,64.60; H, 4.70, N, 15.62.

EXAMPLE 415,5-Bis(4-fluoro-3-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal

To a mixture of3,3-bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal(2.12 g, 5.98 mmoles) and triphenylphosphoranylidene acetaldehyde (1.89g, 6.22 mmoles) under an argon atmosphere was added dry benzene (26 mL).The suspension was quickly warmed to reflux under argon in an oil bath.The solids dissolved very rapidly at the reflux temperature and thecolor became dark brownish. The reaction was allowed to proceed atreflux temperature for a total of 60 minutes. Analytical TLC eluted tentimes with 20% (v/v) ethyl acetate in hexanes showed the desired productat R_(f) =0.35. The crude reaction mixture was poured over a short bedof silica gel and eluted with 2 liters of 20% (v/v) ethyl acetate inhexanes to give 2.12 g (93.3%) of the title compound (TLC homogeneous).MS (CI): m/e=381 for (M+H)⁺ ;

IR (KBr) ν_(max) : 1679 (s), 1606 (s), 1591 (s), 1500 (s), 1438 (m),1250 (s), 1231 (s), 1138 (s), 1125 (s) cm⁻¹ ;

¹ H NMR (CHCl₃) δ: 9.53 (1H, d, J=7.47 Hz), 7.44 (1H, d, J=16.0 Hz),7.15-7.09 (3H, m), 6.9-6.7 (3H, m), 5.80 (1H, dd, J=15.6, 7.44 Hz), 3.55(3H, s), 2.33 (3H, d, J=1.9 Hz), 2.11 (3H, d, J=1.8 Hz);

¹³ C NMR (CDCl₃) δ: 192.51, 162.4 (d, ¹ J_(C-F) =250.7 Hz) 162.0 (d, ¹J_(C-F) =250 Hz), 156.23, 152.57, 147.82, 134.88, 134.83, 134.37, 133.77(d, ³ J_(C-F) =6.04 Hz), 133.19, (d, ³ J_(C-F) =6.04 Hz), 131.94, 130.04(d, ³ J_(C-F) =8.31 Hz), 129.32 (d, ³ J_(C-F) =8.31 Hz), 126.22, 126.00,119.57, 115.66 (d, ² J_(C-F) =23.4 Hz), 115.59 (d, ² J_(C-F) =23.41 Hz),33.64, 14.59, 14.36 ppm;

Anal. Calcd. for C₂₁ H₁₈ F₂ N₄ O: C, 66.31; H, 4.77; N, 14.73. Found: C,66.36; H, 4.71; N, 14.15.

EXAMPLE 42 Ethyl9,9-bis(4-fluoro-3-methylphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate

A solution of the dianion of ethyl acetoacetate (1.42 mL, 11.1 mmoles)in dry tetrahydrofuran (15 mL) was generated as described in Example 10using 450 mg (11.3 mmoles) of NaH (60% in mineral oil) and 4.5 mL (11.1mmoles) of 2.5M n-BuLi in hexane at 0° C. under argon. The orangedianion solution, after being chilled to -78° C., was transferred via acannula into a tetrahydrofuran (15 mL) solution containing5,5-bis(4-fluoro-3-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal(2.12 g, 5.6 mmoles) at -78° C. The reaction mixture was stirred at -78°C. for 15 minutes. Analytical TLC eluted once with 50% (v/v) ethylacetate in hexanes showed a major product at R_(f) =0.16. The reactionmixture was diluted with 20 mL of 1N HCl and the organic residues wereextracted with ethyl acetate (30 mL×2). The organic layers werecombined, dried over MgSO₄ and concentrated under reduced pressure togive a pale syrup. The crude product was chromatographed on a silica gelcolumn eluted with 35% (v/v) ethyl acetate in hexanes to give 1.39 g(48.7%) of the title compound. MS (CI): m/e=511 for (M+H)⁺ ;

IR (KBr) ν_(max) : 3219 (v.s, br), 3000 (s), 1744 (s), 1719 (s), 1500(s), 1325 (m), 1250 (s), 1231 (s), 1119 (s), 1035 (s), 735 (s) cm⁻¹ ;

¹ H NMR(CDCl₃) δ: 7.1-7.0 (3H, m), 6.8-6.6 (3H, m), 6.68 (1H, d, J=15.63Hz), 5.30 (1H, dd, J=5.76, 15.63 (Hz), 4.63 (1H, br), 4.18 (2H, q,J=6.96 Hz), 3.54 (3H, s), 3.44 (2H, s), 2.93 (1H, br, D₂ Oexchangeable), 2.65-2.75 (2H, m), 2.29 (3H, d, J=1.65 Hz), 2.08 (3H, d,J=1.41 Hz), 1.27 (3H, t, J=6.96 Hz);

¹³ C NMR (CDCl₃) δ: 166.66, 161.52 (d, ¹ J_(C-F) =248.40 Hz), 161.13 (d,¹ J_(C-F) =250.66 Hz), 153.53, 148.08, 135.64, 135.26, 135.03, 133.44(d, ³ J_(C-F) =4.53 Hz), 132.71 (d, ³ J_(C-F) =4.53 Hz) 129.58 (d, ³J_(C-F) =8.31 Hz), 128.73 (d, ³ J_(C-F) =7.55 Hz), 128.36, 125.33,125.44, 120.47, 115.21 (d, ² J_(C-F) =21.90 Hz), 67.93, 61.59, 49.86,49.07, 33.56, 14.46 (d, ³ J_(C-F) =11.33 Hz), 14.33, 14.09 ppm;

Anal. Calcd. for C₂₇ H₂₈ F₂ N₄ O₄ H₂ O: C, 61.36; H, 5.72, N, 10.60.Found: C, 62.47; H, 5.59; N, 8.23.

EXAMPLE 43 Ethyl(±)-erythro-9,9-bis(4-fluoro-3-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

The ethyl9,9-bis(4-fluoro-3-methylphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate(1.39 g, 2.7 mmoles) prepared in Example 42 was dissolved in 30 mL oftetrahydrofuran under argon at 0° C. (ice-water bath). To this yellowsolution was added 3 mL (3.0 mmoles) of triethylborane solution intetrahydrofuran (1M in tetrahydrofuran) in one single portion. Thesolution was stirred at 0° C. for one hour before it was chilled to -78°C. (dry ice-acetone bath). To this stirring pale yellow solution wasadded dry NaBH₄ (0.12 g, 3.2 mmoles) and the reaction was allowed toproceed at -78° C. for an additional hour. The crude reaction mixture at-78° C. was diluted with 20 mL of 1N HCl and the cold suspension wasallowed to warm to room temperature. The organic residues were extractedwith ethyl acetate (30 mL×2) and the organic layers were combined, driedover MgSO₄ and concentrated under reduced pressure to give a thicksyrup. The crude material was redissolved into 250 ml of methanol andthe solution was allowed to stand at room temperature for 16 hours.Analytical TLC of the methanolic solution (eluted twice with 50% (v/v)ethyl acetate in hexanes) showed the product at R_(f) =0.10. The productwas purified by silica gel column chromatography eluted with 20% (v/v)ethyl acetate in hexanes. The appropriate fractions were collected togive 0.95 g (68%) of the title compound. MS (CI): m/e=513 for (M+H)⁺ ;

IR (KBr) ν_(max) : 3438 (s), 3000 (s), 1735 (s), 1500 (s), 1441 (s),1250 (s), 1230 (s), 1119 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ: 7.08-7.02 (3H, m), 6.77 (1H, t, J=8.91 Hz), 6.69-6.63(2H, m), 6.66 (1H, d, J=15.7 Hz), 5.31 (1H, dd, J=6.12, 15.7 Hz), 4.42(1H, br) 4.22 (1H, br), 4.16 (2H, q, J=7.2 Hz), 3.80 (1H, br. D₂ Oexchangeable), 3.72 (1H, br. D₂ O exchangeable), 3.56 (3H, s), 2.45 (2H,d, J=6.12 Hz), 2.28 (3H, d, J=1.65 Hz), 2.08 (3H, d, J=1.5 Hz), 1.8-1.57(2H, m), 1.26 (3H, t, J=7.2 Hz);

¹³ C NMR (CDCl₃) δ: 172.47, 161.1 (d, 1_(JC-F) =248.4 Hz), 153.66,147.5, 137.66, 137.31, 135.78, 133.36, 132.68 (d, ³ J_(C-F) =6.04 Hz),129.58 (d, ³ J_(C-F) =8.31 Hz), 128.68 (d, ³ J_(C-F) =8.31 Hz), 127.43,125.50, 115.16 (d, ² J_(C-F) =22.65 Hz), 71.98, 68.40, 60.88, 42.37,41.45, 33.56, 14.53, 14.33, 14.15 ppm;

Anal. Calcd. for C₂₇ H₃₀ F₂ N₄ O₄ : C, 63.27; H, 5.90; N, 10.93. Found:C, 62.80; H, 6.17; N, 10.34.

EXAMPLE 44 Sodium(±)-erythro-9,9-bis(4-fluoro-3-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of ethyl(±)-erythro-9,9-bis(4-fluoro-3-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate(0.80 g, 1.56 mmoles) in tetrahydrofuran (20 mL) at 0° C. under argonwas added 1.0N NaOH solution (1.56 mL) in one single portion. The paleyellow emulsion was stirred at 0° C. (ice-water bath) for two hoursforming a pale transparent solution. Analytical TLC eluted with 20%(v/v) methanol in CHCl₃ showed product at R_(f) =0.16. Most of thevolatile organic solvents were evaporated under reduced pressure and thedesired product was lyophilized under high vacuum to give 0.8 g(quantitative) of the title compound which appears to contain about onemole of water.

IR (KBr) ν_(max) : 3425 (v.br), 1575 (s), 1500 (s), 1438 (s), 1400 (s),1225 (s), 1116 (s) cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ: 7.26-7.19 (3H, m), 6.95 (1H, t, J=8.91 Hz),6.78-6.70 (2H, m), 6.49 (1H, d, J=15.5 Hz), 5.13 (1H, dd, J=5.43, 15.5Hz), 4.15 (1H, br. q, J=6.03 Hz), 3.68 (3H, s), 3.67 (1H, br), 3.45 (2H,v.br, D₂ O exchangeable), 2.26 (3H, br.s), 2.05 (3H, br.s), 2.05 (1H,br), 1.85 (1H, dd, J=8.37, 14 Hz), 1.55-1.25 (2H, m);

¹³ C NMR (DMSO-d₆) δ: 175.09, 159.03 (d, ¹ J_(C-F) =242.36 Hz), 160.08(d, ¹ J_(C-F) =242.36 Hz), 151.84, 144.17, 138.35, 135.01 (d, ³ J_(C-F)=3.78 Hz) 134.12 (d, ³ J_(C-F) =3.02 Hz), 131.83 (d, ³ J_(C-F) =4.53Hz), 130.83 (d, ³ J_(C-F) =3.78 Hz), 128.34 (d, ³ J_(C-F) =8.31 Hz),127.11 (d, ³ J_(C-F) =8.31 Hz), 123.84, 123.52, 123.30, 123.10, 112.87,120.49, 113.99 (d, ² J_(C-F) =22.65 Hz), 113.69 (d, ² J_(C-F) =23.41Hz), 67.66, 65.12, 44.12, 43.24, 33.18, 14.0, 14.15 ppm;

Anal. Calcd. for C₂₅ H₂₅ F₂ N₄ O₄ Na 2H₂ O: C, 55.35; H, 5.39; N, 10.33.Found: C, 55.01; H, 5.01; N, 9.82.

EXAMPLE 45 Ethyl3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenoate andethyl 3,3-bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenoateA. Ethyl3,3-bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenoate

To a solution of 10.0 g (0.028 mole) of ethyl3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate [prepared inExample 2] in 75 mL of N,N-dimethylformamide was added 1.2 g of 60%sodium hydride (0.03 mole) in mineral oil was added. After stirring for0.5 hour, the sodium hydride had dissolved and 8.5 g (0.056 mole) ofiodoethane was added. The solution was stirred at room temperature for16 hours, diluted to 400 mL with water and extracted with CH₂ Cl₂. Theextracts were dried and concentrated in vacuo. The residue wastriturated with hexane to remove mineral oil. The residue was absorbedonto silica gel by dissolving in CH₂ Cl₂ and adding dry silica gel, thenconcentrating in vacuo to a dry powder. This material was transferred tothe top of a silica gel column and eluted with 10% (v/v) ethyl acetatein hexane to give 4.9 g (45.5%) of the title compound; m.p.= 113-114.5°C.

IR (KBr) ν_(max) : 1710 (s), 1601 (s), 1505 (s), 1160 (s), 596 (s), 550(s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ: 7.31-7.28 (m, 2H), 7.11-6.85 (m, 6H), 4.56 (q, 2H),4.10 (q, 2H), 1.51 (t, 3H), 1.02 (t, 3H) ppm;

¹³ C NMR (CDCl₃) δ: 167.03, 165.62 (d), 165.28 (d), 162.64, 160.64 (d),160.34 (d), 152.76, 136.86 (d), 136.00 (d), 131.92 (d), 131.75 (d),131.10 (d), 130.92 (d), 115.53 (d), 115.35 (d), 115.13 (d), 114.96 (d),61.41, 48.31, 14.51, 13.70 ppm;

Anal. Calcd. for C₂₀ H₁₈ F₂ N₄ O₂ : C, 62.50; H, 4.73; N, 14.59. Found:C, 62.28; H, 4.72; N, 14.51.

B. Ethyl3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenoate

The appropriate fractions obtained from continued elution of the silicagel column of Step A with 10% (v/v) ethyl acetate in hexane wereevaporated to yield 5.1 g (47.4%) of the title compound; m.p. 97°-99° C.

IR (KBr) ν_(max) : 1720 (s), 1605 (s), 1507 (s), 1160 (s), 845 (s), 540(s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ: 7.40-6.90 (m, 8H), 4.00 (q, 2H), 3.88 (q, 2H), 1.16(t, 3H), 1.00 (t, 3H) ppm;

Anal. Calcd. for C₂₀ H₁₈ F₂ N₄ O₂ : C, 62.50; H, 4.73; N, 14.58. Found:C, 62.27; H, 4.73; N, 14.51.

EXAMPLE 463,3-Bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenol

To a solution of ethyl3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenoate (1.0g, 2.6 mmoles) at -78° in CH₂ Cl₂ was rapidly added 7.8 mL (7.8 mmoles)of diisobutylaluminum hydride solution (1.0 Molar in methylenechloride). After stirring for 45 minutes, the mixture was quenched with1N HCl solution. The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo. The residual oil was triturated with hexane togive 0.9 g (100%) of the title compound; m.p.=103°-111° C.

¹ H NMR (CDCl₃) δ: 7.41-7.34 (m, 2H), 7.18-7.09 (m, 2H), 6.91-6.87 (m,4H), 4.7 (s, 2H), 3.80 (q, 2H), 1.21 (t, 3H) ppm;

¹³ C NMR (CDCl₃) δ: 166.04, 165.91 (d), 165.47 (d), 161.08, 160.84,156.02, 135.78 (d), 134.22 (d), 131.73 (d), 131.69 (d), 131.55 (d),131.51 (d), 116.01 (d), 115.94 (d), 115.57 (d), 115.50 (d), 61.91,42.85, 14.13 ppm;

Anal. Calcd. for C₁₈ H₁₆ F₂ N₄ O: C, 63.16; H, 4.72; N, 16.37. Found: C,62.99; H, 4.73; N. 16.40.

EXAMPLE 473,3-Bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenol

The general procedure of Example 46 was repeated, except that the ethyl3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenoateutilized therein was replaced with 1.0 g of ethyl3,3-bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenoate andthere was thereby produced 0.9 g of the title compound; m.p.=82°-84° C.

¹ H NMR (CDCl₃) δ: 7.30-7.33 (m, 2H), 7.08-6.87 (m, 6H), 4.57 (d, 2H),4.48 (d, 2H), 2.88 (t, 1H), 1.43 (t, 1H);

¹³ C NMR (CDCl₃) δ: 165.04, 164.82 (d), 164.67 (d), 160.12, 159.78,147.08, 137.56 (d), 136.45 (d), 131.47 (d), 131.43 (d), 131.34 (d),131.25 (d), 115.53 (t), 115.13 (t), 114.72 (d), 62.89, 48.24, 14.40 ppm;

Anal. Calcd. for C₁₈ H₁₆ F₂ N₄ O: C, 63.16; H, 4.72; N, 16.37. Found: C,63.22; H, 4.74; N. 16.41.

EXAMPLE 483,3-Bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenal

Pyridinium chlorochromate (0.9 g) was added to a solution of 0.8 g (2.3mmoles) of the3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenol inmethylene chloride. The solution became bright yellow and then darkenedwith the formation of a dark gummy precipitate. After stirring at roomtemperature for 16 hours, the mixture was poured directly onto a silicagel column and eluted with methylene chloride to give 0.65 g (83%) ofthe title compound; m.p.=144°-145° C.

IR (KBr) ν_(max) : 1680 (s), 1600 (s), 1515 (s), 1135 (s), 855 (s), 840(s);

¹ H NMR (CDCl₃) δ: 9.65 (1H, s), 7.36-7.20 (4H, m), 7.05-6.88 (4H, m),4.01 (2H, q), 1.38 (3H, t);

¹³ C NMR (CDCl₃) δ: 189.02, 167.07 (d), 166.51 (d), 164.68, 162.04,150.41, 133.65 (d), 133.49 (d), 132.34 (d), 132.18 (d), 124.11, 116.46(d), 116.34 (d), 116.02 (d), 115.90 (d), 43.00, 14.34 ppm;

Anal. Calcd. for C₁₈ H₁₄ F₂ N₄ O: C, 63.53; H, 4.15; N, 16.47. Found: C,62.90, H, 4.13; N, 16.37.

EXAMPLE 493,3-Bis(4-Fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenal

The reaction of 4.0 g (12.0 mmoles) of3,3-bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenol withpyridinium chlorochromate (4.5 g) was carried out by the proceduredescribed in Example 48 and there was thereby produced 3.25 g (79.7%) ofthe title compound; m.p.=138°-139° C.

¹ H NMR (CDCl₃) δ: 9.70 (1H, s), 7.39-7.32 (2H, m), 7.23-7.14 (2H, m),7.04-6.86 (4H, m), 4.62 (2H, q), 1.56 (3H, t);

¹³ C NMR (CDCl₃) δ: 190.04, 166.71 (d), 165.86 (d), 163.01, 161.68,161.16 (d), 160.86 (d), 135.62 (d), 135.55 (d), 133.69 (d), 133.53 (d),132.37 (d), 137.19 (d), 127.74, 116.06 (t), 115.59 (t), 115.17 (t),48.45, 14.59 ppm;

Anal. Calcd. for C₁₈ H₁₄ F₂ N₄ O: C, 63.53; H, 4.15; N, 16.47. Found: C,63.53, H, 4.11; N, 16.74.

EXAMPLE 505,5-Bis(4-fluorophenyl)-4-(1-ethyl-1H-tetrazol-5-yl)-2,4-pentadienal

A solution of3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenal (0.65 g,1.9 mmoles) and 0.64 g (2.1 mmoles) of triphenylphosphoranylideneacetaldehyde in benzene was heated at reflux temperature for 2 hours.The solution was concentrated in vacuo and the residue purified bysilica gel column chromatography eluting with CH₂ Cl₂ to give 0.55 g(79.7%) of the title compound, m.p.=163°-165° C.

¹ H NMR (CDCl₃) δ: 9.54 (1H, d), 7.49 (1H, d), 7.42-6.96 (8H, m), 5.76(1H, dd), 8.89 (2H, q), 1.27 (3H, t);

¹³ C NMR (CDCl₃) δ: 192.41, 166.21 (d), 165.77 (d), 161.18, 160.71,155.04, 151.58, 150.10, 148.34, 148.27, 147.91, 138.90, 134.97, 134.53,132.77, 132.60, 132.20, 132.03, 120.35, 116.43, 116.26, 116.03, 115.78,42.66, 14.30 ppm;

Anal. Calcd. for C₂₀ H₁₆ F₂ N₄ O: C, 65.57; H, 4.41; N, 15.30. Found: C,65.32; H, 4.77; N, 14.76.

EXAMPLE 515,5-Bis(4-fluorophenyl)-4-(2-ethyl-2H-tetrazol-5-yl)-2,4-pentadienal

The procedure of Example 50 was repeated using 3.25 g (9.5 mmoles) of3,3-bis(4-fluorophenyl)-2-(2-ethyl-2H-tetrazol-5-yl)-2-propenal and 3.05g (10.0 mmoles) of triphenylphosphoranylidene acetaldehyde and there wasthereby produced 3.3 g (95%) of the title compound; m.p.=117°-120° C.

¹ H NMR (CDCl₃) δ: 9.54 (1H, d), 7.49 (1H, d), 7.34-7.11 (4H, m),7.00-6.78 (4H, m), 5.94 (1H, dd), 4.60 (2H, q), 1.52 (3H,t);

¹³ C NMR (CDCl₃) δ: 193.23, 165.83, 165.08, 162.91, 160.83, 160.10,154.47, 151.28, 149.46, 140.21, 132.89, 132.72, 132.13, 132.00, 130.56,116.00, 115.56, 115.28, 114.89, 48.46, 14.63 ppm;

Anal. Calcd. for C₂₀ H₁₀ F₂ N₄ O: C, 65.57; H, 4.41; N, 15.30. Found: C,65.36; H, 4.40; N, 15.64.

EXAMPLE 52 Ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1-ethyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate

To a solution of 0.5 g (1.4 mmoles) of5,5-bis(4-fluorophenyl)-4-(1-ethyl-1H-tetrazol-5-yl)2,4-pentadienal intetrahydrofuran at -50° C., was added 1.75 mL of 0.8M (1.4 mmoles) of afreshly prepared solution of ethyl acetoacetate dianion [described inExample 10]. The solution was stirred for 30 minutes at -50° C. and thenallowed to warm to -10° C. during the next 30 minutes. The solution wasquenched with 1N HCl and extracted with methylene chloride. The organicextracts were dried and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with chloroform to give 0.4g of the title compound as an oil. MS (CI): m/e=497 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.29-7.11 (4H, m), 6.87-6.83 (4H, m), 6.72 (1H, d),5.24 (1H, dd), 4.62 (1H, m), 4.16 (2H, q), 3.88 (2H, q), 3.44 (2H, s),3.30 (1H, d), 2.71 (2H, d), 1.25 (3H, t) ppm;

¹³ C NMR (CDCl₃) δ: 166.69, 165.31, 164.92, 160.32, 159.95, 152.64,146.82, 136.7, 135.98, 135.34, 135.26, 135.18, 132.38, 132.20, 131.62,131.45, 128.26, 121.25, 115.92, 115.78, 115.48, 115.34, 91.48, 67.75,61.51, 49.87, 49.14, 42.55, 14.27, 14.09 ppm.

EXAMPLE 53 Ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-(2-ethyl-2H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate

To a solution of5,5-bis(4-fluorophenyl)-4-(2-ethyl-2H-tetrazol-5-yl)-2,4-pentadienal(2.0 g) in 20 mL of tetrahydrofuran at -40° C. was added 6.9 mL of 0.8M(5.5 mmoles) freshly prepared solution of ethyl acetoacetate dianion[described in Example 10]. The solution was stirred at -40° C. for 30minutes and then allowed to warm to -10° C. After a total of one hour,the reaction was quenched with 1N HCl. The mixture was extracted withchloroform, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography to give 0.4 g of pure titlecompound. MS (EI): m/e=496 for M⁺ ;

¹ H NMR (CDCl₃) δ: 7.29-7.22 (2H, m), 7.13-7.04 (2H, m), 6.90-6.78 (4H,m), 6.71 (1H, d), 4.68-4.48 (3H, m), 4.15 (2H, q), 3.45 (2H, s), 2.73(3H, d with broad shoulder), 1.49 (3H, t), 1.27 (3H, t) ppm;

¹³ C NMR (CDCl₃) δ: 164.95, 164.28, 163.91, 159.99, 159,39, 145.98,137.64, 137.56, 136.20, 136.06, 135.21, 132.42, 132.25, 131.71, 131.53,128.90, 115.54, 115.10, 114.93, 114.48, 91.31, 68.11, 61.44, 49.93,49.36, 48.28, 14.62, 14.10 ppm;

An additional quantity of 1.55 g of crude title compound was alsoobtained which was used without further purification.

EXAMPLE 54 Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-ethyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1-ethyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate(0.5 g, 1.0 mmole) in tetrahydrofuran at 0° C. was added 1.1 mL (1.1mmoles) of triethylborane solution (1.0M solution in tetrahydrofuran).The solution was stirred for 2.5 hours and then cooled to -78° C. Sodiumborohydride (0.08 g, 2.0 mmoles) was added followed by 0.5 mL ofmethanol. After stirring for 2.5 hours at -78° C., the mixture wasdiluted with an equal volume of hexane and quenched with 1N HCl followedby extractions with ethyl acetate. The organic extracts were dried(MgSO₄) and concentrated in vacuo and then dissolved in methanol andstirred at room temperature for 16 hours. The solution was concentratedin vacuo and the product was purified by silica gel columnchromatography eluting with 2% methanol in chloroform to give 0.3 g ofthe title compound as an oil. MS (EI): m/e=498 for M⁺ ;

¹ H NMR (CDCl₃) δ: 7.27-7.13 (4H, m), 6.88-6.84 (4H, m), 6.71 (1H, d),5.28 (1H, dd), 4.18 (1H, m), 4.17 (3H, q over broad m), 3,88 (2H, q),3.71 (2H, dd), 2.45 (2H, d), 1.59 (3H, t), 1.28 (3H, t), ppm.

¹³ C NMR (CDCl₃) δ: 172.37, 165.26, 164.87, 160.31, 159.90, 146.38,137.77, 135.89, 135.82, 135.28, 132.29, 132.17, 131.61, 131.43, 127.39,121.48, 115.89, 115.75, 115.49, 115.30, 71.80, 60.86, 42.48, 42.25,41.47, 14.26, 14.28 ppm.

EXAMPLE 55 Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-ethyl-2H-tetrazol-5-yl)-6,8-nonadienoateand ethyl(±)-erythro-7,7-bis(4-fluorophenyl)-3,5-dihydroxy-6-(2-ethyl-2H-tetrazol-5-yl)-6-heptenoateA. Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-ethyl-2H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of 1.55 g (3.0 mmoles) of crude ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-(2-ethyl-2H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate(prepared in Example 53) in tetrahydrofuran at 0° C. was added 3.3 mL(3.3 mmoles) of 1M triethylborane solution (1.0M solution intetrahydrofuran). After stirring for 2.5 hours, the solution was cooledto -78° C. and 0.25 g (6.3 mmoles) of sodium borohydride followed by 1.2mL of methanol were added. After stirring for an additional 2.5 hours,the reaction mixture was diluted with an equal volume of hexane andquenched with 1N HCl. The mixture was extracted with ethyl acetate andthe combined organic phase was dried (MgSO₄) and concentrated in vacuo.The residue was dissolved in methanol and stirred at room temperaturefor 16 hours. The methanol solution was concentrated in vacuo and theresidue purified by silica gel chromatography eluting with 1% CH₃ OH inCHCl.sub. 3. The appropriate fractions were combined and evaporatedunder reduced pressure to give 0.64 g of the title compound as an oil.MS (EI): m/e=498 for M⁺ ;

¹ H NMR (CDCl₃) δ: 7.30-7.02 (4H, m), 6.80-6.72 (4H, m), 6.68 (1H, d),5.45 (4H, dd), 4.52 (2H, q), 4.48 (1H, m), 4.15 (3H, q over m), 3.72(1H, m), 2.45 (2H, dd), 1.67 (2H, m), 1.45 (3H, t), 1.25 (3H, t) ppm;

¹³ C NMR (CDCl₃) δ: 164.92, 164.29, 164.11, 163.99, 159.98, 159.34,145.65, 141.24, 137.69, 134.64, 136.83, 136.29, 136.21, 132.39, 132.23,131.69, 131.51, 128.40, 125.09, 115.53, 115.10, 114.93, 114.51, 72.17,68.09, 60.78, 48.26, 42.50, 41.66, 14.68, 14.19 ppm.

B. Ethyl(±)-erythro-7,7-bis(4-fluorophenyl)-3,5-dihydroxy-6-(2-ethyl-2H-tetrazol-5-yl)-6-heptenoate

The appropriate fractions from the elution of the silica gel column inStep A were combined and evaporated to give 0.2 g of the title compound;m.p. 124°-128° C. MS (EI): m/e=473 for MH⁺ ;

¹ H NMR (CDCl₃) δ: 7.32-6.78 (8H, m), 4.93 (1H, m), 4.55 (2H, q), 4.17(3H, q over m), 3.88 (1H, d), 3.64 (1H, d), 2.45 (2H, dd), 1.83 (2H, m),1.46 (3H, t), 1.27 (3H, t) ppm;

¹³ C NMR (CDCl₃) δ: 177.18, 164.94, 164.44, 163.16, 160.01, 159.51,146.58, 137.11, 137.05, 135.92, 135.86, 131.31, 131.15, 130.98, 127.98,115.73, 115.31, 115.01, 114.58, 71.44, 68.56, 67.86, 65.28, 60.72,48.33, 42.44, 41.74, 41.44, 41.36, 14.53, 14.21 ppm;

Anal. Calcd. for C₂₄ H₂₆ F₂ N₄ O₄ 0.5 H₂ O: C, 59.87; H, 5.66; N, 11.64.Found: C, 59.62; H, 5.62; N, 11.21.

EXAMPLE 56 Sodium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-ethyl-1H-tetrazol-5-yl)-6,8-nonadienoate

A solution of 1.0 g (2.0 mmoles) of ethyl9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-ethyl-1H-tetrazol-5-yl)-6,8-nonadienoateand 2 mL (2.0 mmoles) 1N sodium hydroxide in 25 mL of ethanol wasstirred for 45 minutes. The reaction mixture was concentrated in vacuoand the residue was dissolved in water. The aqueous solution waslyophilized in vacuo to yield the title compound which appears tocontain about one mole of water; m.p.=193°-203° C. MS (FAM): m/e=493 for(M+H)⁺ ;

IR (KBr) ν_(max) : 3200 (v.br), 1650 (br), 1600 (s), 1580 (s), 1510 (s),1410 (br), 1230 (s), 850 cm⁻¹ ;

¹ H NMR (CDCl₃) δ: 7.37-7.29 (4H, m), 7.05-6.88 (4H, m), 6.50 (1H, d),5.08 (1H, dd), 4.12 (1H, m), 4.04 (2H, q), 3.62 (1H, m), 3.35 (2H),2.03-1.78 (2H, m), 1.46-1.23 (2H, m), 1.18 (3H, t) ppm;

Anal. Calcd. for C₂₄ H₂₃ F₂ N₄ O₄ Na H₂ O: C, 56.48; H, 4.94; N, 10.98.Found: C, 56.28; H, 4.96; N, 10.56.

EXAMPLE 57 Sodium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-ethyl-2H-tetrazol-5-yl)-6,8-nonadienoate

A solution of 0.65 g (1.3 mmoles) of ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-ethyl-2H-tetrazol-5-yl)-6,8-nonadienoateand 1.3 mL (1.3 mmoles) 1N sodium hydroxide solution in 25 mL ethanolwas stirred for 1 hour. The reaction solution was concentrated in vacuoand the residue was dissolved in water. The aqueous solution waslyophilized in vacuo to yield the title compound; m.p.=170°-190° C. MS(FAB): m/e=493 for (M+H)⁺ ;

IR (KBr) ν_(max) : 3200 (v.br), 1650 (br), 1605 (s), 1580 (s), 1512 (s),1410 (br), 1230 (s), 850 (s) cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ: 7.34-6.79 (8H, m), 6.50 (1H, d), 5.31 (1H, dd), 5.0(1H, br.m), 4.58 (2H, q), 4.13 (1H, m), 3.63 (1H, m), 3.35 (1H, br.m),2.03-1.78 (2H, m), 1.46-1.21 (2H, m), 1.34 (3H, t) ppm.

Anal. Calcd. for C₂₄ H₂₃ F₂ N₄ O₄ Na 1.3 H₂ O: C, 55.88; H, 5.00; N,10.86. Found: C, 55.41; H, 4.67; N, 10.54.

EXAMPLE 58 Sodium(±)-erythro-7,7-bis(4-fluorophenyl)-3,5-dihydroxy-6-(2-ethyl-2H-tetrazol-5-yl)-6-heptenoate

A solution of 0.2 g (0.45 mmoles) of ethyl(±)-erythro-7,7-bis(4-fluorophenyl)-3,5-dihydroxy-6-(2-ethyl-2H-tetrazol-5-yl)-6-heptenoate(prepared in Example 55, Step B) and 0.45 mL (0.45 mmoles) 1N sodiumhydroxide solution in 10 mL ethanol was stirred for 1 hour. The reactionsolution was concentrated under reduced pressure and the residue wasdissolved in methanol. The aqueous solution was lyophilized in vacuo toyield the title compound.

¹ H NMR (CDCl₃) δ: 7.3-6.7 (8H, m), 5.7 (2H, br.m), 4.8 (1H, m), 4.4(2H, q), 3.9 (1H, m), 3.65 (1H, m), 2.7 (2H, m), 1.9 (2H, m), 1.2 (3H,t) ppm;

¹³ C NMR (CDCl₃) δ: 179.64, 164.64, 164.26, 163.27, 163.59, 159.71,159.35, 145.67, 137.52, 137.46, 136.06, 135.98, 131.34, 131.20, 129.12,115.65, 115.22, 114.86, 114.44, 70.30, 58.26, 48.18, 18.41, 14.48 ppm;

Anal. Calcd for C₂₂ H₂₁ F₂ N₄ O₄ Na 2H₂ O: C, 52.59; H, 5.02; N, 11.16.Found: C, 52.81; H, 5.32; N, 9.64.

EXAMPLE 591,1-Bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol.

A solution of 1,5-dimethyltetrazol (8.9 g, 91.0 mmoles) in 100 mL of drytetrahydrofuran at -60° C. was treated with n-butyl lithium (48 mL of1.89M solution, 91.0 mmoles). After stirring for 20 minutes,2,2',4,4'-tetramethylbenzophenone (18 g, 76 mmoles) [prepared by theprocedure described in J. Am. Chem. Soc., 81, 4858 (1959)] in 50 mL drytetrahydrofuran was added and the solution was stirred for 1 hour duringwhich time it was allowed to warm to -20° C. The reaction was quenchedwith 1N HCl, then extracted with chloroform. The combined organicextracts were dried (MgSO₄) and evaporated to give 22 g of the titlecompound; m.p.=175°-177° C.

IR (KBr) ν_(max) : 3390 (br), 1620 (s), 1460 (s), 1200 (s), 820 (s) cm⁻¹;

¹ H NMR (CDCl₃) δ: 7.26 (2H, d), 6.95-6.83 (4H, m), 4.00 (1H, s), 3.82(2H, s), 3.41 (3H, s), 2.23 (6H, s), 1.83 (6H, s) ppm;

¹³ C NMR (CDCl₃) δ: 152.34, 139.28, 137.32, 135.79, 133.24, 126.26,125.92, 77.47, 35.04, 32.99, 21.28, 20.76 ppm;

Anal. Calcd. for C₂₀ H₂₄ N₄ O: C, 71.41; H, 7.20; N, 16.67. Found: C,70.82; H, 7.26; N, 16.45.

EXAMPLE 601,1-Bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene.

A mixture of1,1-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (1.8 g,5.4 mmoles) and potassium hydrogen sulfate (100 mg) was placed in an oilbath preheated to 190° C. After 15 minutes, the melt was cooled andmethylene chloride added to the residue. The insolubles were removed andthe solution evaporated. The residue was crystallized from isopropylether to give 1.2 g of the title compound; m.p.=143°-143.5° C.

IR (KBr) ν_(max) : 2930 (s), 1635 (s), 1620 (s), 1510 (s), 1450 (s), 820(s), 740 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ: 7.15-6.80 (6H, m), 6.60 (1H, s), 3.40 (3H, s), 2.36(3H, s), 2.30 (3H, s), 2.18 (3H, s), 1.85 (3H, s) ppm;

¹³ C NMR (CDCl₃) δ: 154.18, 152.21, 138.54, 138.38, 138.06, 135.67,135.40, 135.18, 131.78, 131.72, 129.90, 129.66, 126.77, 126.55, 111.99,33.65, 21.02, 20.69, 19.95 ppm;

Anal. Calcd. for C₂₀ H₂₂ N₄ : C, 75.45; H, 6.97; N, 17.60. Found: C,75.04; H, 7.03; N, 17.63.

EXAMPLE 613,3-Bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

A solution of1,1-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (1.0 g,3.1 mmoles) in 10 mL dry tetrahydrofuran was treated with n-butyllithium (1.64 mL of 1.89M solution, 3.1 mmoles) at -78° C. Afterstirring with cooling for 30 minutes, ethyl formate (0.3 g, 4.0 mmoles)was added and the mixture stirred with cooling for 2 hours. The reactionwas quenched with 1N HCl and extracted with chloroform. The combinedorganic fractions were dried (MgSO₄) and evaporated. The residue waspurified by column chromatography on silica gel eluting with 10% (v/v)ethyl acetate in hexane to give 0.9 g of product as an oil. Triturationof the oil with isopropyl ether gave the title compound as a solid;m.p.=117°-120° C. MS (CI): m/e=347 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 9.58 (1H, s), 7.25-6.78 (7H, m), 3.70 (3H, s), 2.40(3H, s), 2.25 (3H, s), 2.20 (3H, s), 1.90 (3H, s) ppm;

¹³ C NMR (CDCl₃) δ: 189.49, 168.80, 151.05, 140.87, 140.26, 137.06,135.86, 134.87, 133.28, 132.04, 129.60, 126.62, 125.28, 34.17, 21.21,21.06, 20.37, 20.07 ppm;

Anal. Calcd. for C₂₁ H₂₂ N₄ O: C, 72.81; H, 6.41; N, 16.18; Found: C,72.99; H, 6.43; N, 16.09.

EXAMPLE 625,5-Bis(2,4-dimethylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal

A solution of3,3-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal(4.5 g, 13.0 mmoles) and triphenylphosphoranylidene acetaldehyde (4.1 g,13.0 mmoles) in benzene was heated at reflux temperature for 6 hours.The reaction mixture was evaporated under reduced pressure and theresidue was purified by column chromatography on silica gel eluting with10% (v/v) ethyl acetate in hexane to give 5.9 g of the title compound asan oil. MS (CI): m/e=373 for (M+H)⁺ ;

IR (KBr) ν_(max) : 1742 (s), 1680, 1615, 1450 (s), 1130 (s), 830 (s),810 (s) cm⁻¹ ;

¹ H NMR (CDCl₃) δ: 9.42 (1H, d), 7.3 (1H, d), 7.14-6.85 (6H, m), 5.80(1H, dd), 3.52 (3H, s), 2.35 (3H, s), 2.20 (6H, s), 1.85 (3H, s) ppm;

¹³ C NMR (CDCl₃) δ: 192.53, 158.44, 152.18, 150.60, 148.18, 139.45,139.25, 136.14, 135.98, 135.18, 134.63, 131.78, 131.70, 131.28, 130.10,126.45, 126.25, 121.26, 33.61, 20.90, 20.71, 20.18, 20.11 ppm;

Anal. Calcd. for C₂₃ H₂₄ N₄ O: C, 74.17; H, 6.50; N, 15.05. Found: C,72.82; H, 6.85; N, 13.33.

EXAMPLE 63 Ethyl9,9-bis(2,4-dimethylphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonedienoate

The general procedure of Example 42 was repeated, except that the5,5-bis(4-fluoro-3-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienalutilized therein was replaced with 5.9 g (16.0 mmoles) of5,5-bis(2,4-dimethylphenyl)-4-(1-methyl-1H-tetrazol-5yl)-2,4-pentadienaland the crude material that was thereby produced was purified by silicagel column chromatography eluting with 1% (v/v) methanol in methylenechloride to give 4 g of the title compound.

¹ H NMR (CDCl₃) δ: 7.10-6.95 (3H, m), 6.83-6.75 (3H, m), 6.50 (1H, d),5.30 (1H,dd), 4.60 (1H, m), 4.14 (2H, q), 3.60 (3H, s), 3.43 (2H, s),3.0 (1H, bs), 2.70 (2H, d), 2.35 (3H, s), 2.20 (3H, s), 1.90 (3H, s),1.28 (3H, t) ppm;

¹³ C NMR (CDCl₃) δ: 202.15, 166.59, 153.39, 149.71, 138.17, 136.15,135.98, 135.81, 135.32, 134.96, 131.63, 131.42, 130.34, 130.04, 128.22,126.36, 126.21, 122.03, 67.91, 61.34, 49.79, 49.24, 33.76, 21.06, 20.89,20.49, 20.28, 14.02 ppm;

Anal. Calcd. for C₂₉ H₃₄ N₄ O₄ : C, 69.31; H, 6.82; N, 11.15. Found: C,68.29; H, 6.91; N, 10.88.

EXAMPLE 64 Ethyl(±)-erythro-9,9-bis(2,4-dimethylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

The general procedure of Example 43 was repeated, except that the ethyl9,9-bis(4-fluoro-3-methylphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoateutilized therein was replaced with 4 g (8.0 mmoles) of ethyl9,9-bis(2,4-dimethylphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoateand the crude material that was thereby produced was purified by silicagel column chromatography eluting with 1% (v/v) methanol in methylenechloride to give 2.5 g of the title compound. MS (CI): m/e=505 for(M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.10-6.90 (3H, m), 6.85-6.68 (3H, m), 6.43 (1H, d),5.30 (1H, dd), 4.40 (1H, m), 4.35-4.08 (3H, q over m), 3.90 (1H, s),3.78 (1H, s), 3.58 (3H, s), 2.47 (2H, d), 2.30 (3H, s), 2.15 (6H, s),1.88 (3H, s), 1.60 (2H, m), 1.25 (3H, t) ppm;

¹³ C NMR (CDCl₃) δ: 172.23, 153.67, 149.39, 149.31, 138.18, 136.87,136.14, 135.95, 135.52, 131.75, 131.54, 130.17, 127.62, 126.47, 126.32,122.37, 72.05, 68.26, 60.76, 42.48, 41.70, 33.86, 21.18, 21.00 20.64,20.40, 14.21 ppm;

Anal. Calcd. for C₂₉ H₃₆ N₄ O₄ : C, 69.03; H, 7.20; N, 11.11. Found: C,68.13; H, 7.25; N, 10.84.

EXAMPLE 65 Sodium(±)-erythro-9,9-Bis(2,4-dimethylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of ethyl(±)-erythro-9,9-bis-(2,4-dimethylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate(2.5 g, 4.95 mmoles) in ethanol was added sodium hydroxide solution(4.95 mL of 1.0N solution, 4.95 mmoles). After stirring for 1.5 hours,analytical TLC eluted with 25% (v/v) ethyl acetate in hexane showed nostarting material. The solution was concentrated in vacuo and thedesired product was lyophilized under high vacuum to produce the titlecompound as a beige powder. MS (FAB): m/e=498 for M+;

IR (KBr) ν_(max) : 3200 (v.br), 1620 (shoulder), 1580 (br), 1450, 1410,705 (s) cm⁻¹ ;

¹ H NMR (D₂ 0) δ: 6.93-6.41 (6H, m), 6.31 (1H, d), 5.21 (1H, dd),4.23-4.17 (1H, m), 3.93 (1H, m), 3.66 (3H, s), 3.59 (2H, q), 2.31-2.10(2H, m), 2.01 (3H, s), 1.73 (3H, s), 1.67 (3H, s), 1.65-1.48 (1.5H, m),1.12 (≃2H, t) ppm;

Anal. Calcd. for C₂₇ H₃₁ N₄ O₄ Na 0.7 mole EtOH: C, 64.27; H, 6.69; N,10.56 Found: C, 64.48; H, 6.84; N, 10.56.

EXAMPLE 66 Ethyl3,3-bis(4-fluorophenyl)-2-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2-propenoateand ethyl3,3-bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenoate

Sodium hydride (0.67 g of 60% in mineral oil, 14.0 mmoles) was added toa solution of ethyl3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate (5.0 g, 14.0mmoles) [prepared in Example 2] in dimethylformamide (50 mL) and themixture stirred to give a clear solution. MEM chloride(2-methoxyethoxymethyl chloride) (3.5 g, 28.0 mmoles) was then added andthe mixture stirred for 64 hours. The mixture was diluted with water(200 mL) and extracted with methylene chloride. The organic extractswere dried (MgSO₄) and the solution concentrated in vacuo to give 6 g ofthe title compounds as an oil in approximately 1:1 ratio as ascertainedby ¹ H NMR. MS (CI): m/e=445 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.29-6.84 (8H, m), 5.84 (2H, s), 5.43 (2H, s), 4.06(2H, m), 3.53-3.40 (4H, m), 3.37 (3H, s), 0.99 (3H, m) ppm;

¹³ C NMR (CDCl₃) δ: 166.23, 165.90, 165.78, 165.59, 165.12, 163.15,162.34, 160.93, 160.77, 160.62, 160.20, 157.36, 153.61, 152.20, 136.66,136.61, 135.94, 135.88, 134.53, 134.45, 132.20, 132.03, 131.88, 131.73,131.19, 131.03, 130.87, 120.04, 115.85, 115.66, 115.49, 115.42, 115.22,115.05, 114.96, 95.54, 92.21, 80,97, 76.79, 71.69, 71.10, 70,95, 69.53,69.09, 67.37, 66.73, 61.70, 61.38, 58.89, 36.35, 31.30, 27.80, 26.76,17.65, 13.60, 13.52 ppm;

EXAMPLE 673,3-Bis(4-fluorophenyl)-2-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2-propenoland3,3-bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenol

A solution of diisobutylaluminum hydride (65 mL of 1M solution, 65.0mmoles) in methylene chloride was added to a solution containing ethyl3,3-bis(4-fluorophenyl)-2-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2-propenoateand ethyl3,3-bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenoate(6.0 g, 13.0 mmoles) [prepared in Example 66] in methylene chloride (50mL) at -78° C. After stirring for 3 hours at -78° C., the reaction washydrolyzed by the addition of excess 1N HCl. The aqueous layer wasseparated and extracted with methylene chloride. The combined organicextracts were dried and concentrated in vacuo to give 5.2 g of the titlecompounds as an oil in approximately 1:1 ratio as ascertained by ¹ HNMR. MS (EI): m/e=402 for M⁺ ;

Anal. Calcd. for C₂₀ H₂₀ F₂ N₄ O₃ : C, 59.70; H, 5.02; N, 13.93. Found:C, 59.89; H, 5.09; N, 13.99.

EXAMPLE 683,3-Bis(4-fluorophenyl)-2-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2-propenaland3,3-bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenal

Pyridinium chlorochromate (6.6 g) was added to a solution containing3,3-bis(4-fluorophenyl)-2-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2-propenoland3,3-bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenol(5.2 g, 13.0 mmoles) [prepared in Example 67] in methylene chloride.After stirring for 18 hours at room temperature, the reaction haddarkened with formation of a gummy precipitate. The reaction mixture wasdecanted and the methylene chloride solution was concentrated in vacuo.The residue was purified by column chromatography on silica gel elutingwith methylene chloride to give 3 g of the title compounds as an oil inapproximately 1:1 ratio, as ascertained by ¹ H NMR. MS (EI): m/e=400 forM⁺ ;

¹ H NMR (CDCl₃) δ: 9.73 (1H, s), 9.60 (1H, s), 7.44-6.91 (9H, m), 5.92(2H, s), 5.57 (2H, s), 3.68-3.38 (7H, m) ppm;

¹³ C NMR (CDCl₃) δ: 189.62, 188.78, 166.87, 166.57, 166.34, 165.68,165.60, 163.17, 161.85, 161.65, 161.55, 161.29, 160.66, 151.11, 134.39,134.33, 133.43, 133.55, 133.37, 133.08, 132.42, 132.25, 132.06, 129.34,129.19, 128.96, 127.22, 123.65, 116.12, 115.94, 115.69, 115.50, 115.26,115.07, 80.92, 77.01, 70.87, 69.40, 69.26, 68.83, 62.06, 58.78, 50.23,46.41 ppm;

Anal. Calcd. for C₂₀ H₁₈ F₂ N₄ O₃ : C, 60.00; H, 4.54; N, 13.99. Found:C, 58.11, H, 4.65; N, 13.19.

EXAMPLE 693,3-Bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenaland5,5-bis(4-fluorophenyl)-4-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2,4-pentadienalA.3,3-Bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenal

A solution containing3,3-bis(4-fluorophenyl)-2-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2-propenaland3,3-bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenal(3.5 g, 8.75 mmoles) [prepared in Example 68] andtriphenylphosphoranylideneacetaldehyde (1.33 g, 4.4 mmoles) in benzene(50 mL) was heated at reflux temperature for 6 hours. The reactionmixture was concentrated in vacuo and the residue purified by columnchromatography on silica gel eluting with 15% (v/v) ethyl acetate inhexane. Concentration of the appropriate fractions yielded an effectiveseparation and isolation of unreacted title compound. MS (CI): m/e=401for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 9.70 (1H, s), 7.40-6.80 (9H, m), 5.85 (2H, s),3.60-3.40 (4H, m), 3.35 (3H, s) ppm;

¹³ C NMR (CDCl₃) δ: 189.66, 166.66, 165.76, 163.21, 161.72, 163.21,161.72, 161.64, 160.75, 149.10, 135.46, 135.38, 133.61, 133.44, 133.27,133.16, 132.79, 132.64, 132.31, 132.14, 131.94, 131.86, 127.32, 116.01,115.91, 115.56, 115.14, 80.99, 70.91, 69.46, 58.89 ppm;

B.5,5-Bis(4-fluorophenyl)-4-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2,4-pentadienal

Continued elution of the silica gel column from the above Step A yieldedthe desired product. The appropriate fractions were combined andevaporated under reduced pressure to yield 1.1 g of the title compound.MS (CI): m/e=427 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 9.60 (1H, d), 7.45 (1H, d), 7.38-6.80 (8H, m), 5.70(1H, dd), 5.30 (2H, s), 3.68-3.40 (4H, m) 3.30 (3H, s) ppm;

¹³ C NMR (CDCl₃) δ: 192.42, 166.17, 165.72, 161.16, 160.70, 155.23,152.49, 147.96, 135.04, 134.96, 134.55, 134.48, 132.90, 132.73, 132.21,132.04, 131.85, 119.94, 116.31, 116.08, 115.87, 115.64, 76.67, 71.01,69.53, 58.96 ppm.

EXAMPLE 705,5-Bis(4-fluorophenyl)-4-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2,4-pentadienal

A solution of3,3-bis(4-fluorophenyl)-2-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2-propenal(1.4 g, 3.5 mmoles) and triphenylphosphoranylideneacetaldehyde (1.3 g,4.3 mmoles) [isolated in Example 69, Step A] in 25 mL of benzene washeated at reflux temperature for 12 hours. The reaction mixture wasevaporated under reduced pressure and the residue purified by columnchromatography on silica gel eluting with 20% (v/v) ethyl acetate inhexane to give 0.9 g of the title compound as an oil. MS (CI): m/e=427for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 9.52 (1H, d), 7.48 (1H, d), 7.32-7.10 (4H, m),6.92-6.75 (4H, m), 5.85 (3H, s over dd), 3.6-3.5 (4H, m), 3.35 (3H, s)ppm;

¹³ C NMR (CDCl₃) δ: 193.07, 165.85, 165.04, 163.50, 160.85, 160.07,154.72, 149.12, 136.61, 136.59, 135.29, 135.24, 133.64, 133.47, 132.84,132.67, 132.35, 132.13, 131.96, 131.91, 123.79, 115.99, 115.55, 115.35,114.93, 81.12, 70,96, 69.55, 58.98 ppm.

EXAMPLE 71 Ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-3-oxo-6,8-nonadienoate

Ethyl acetoacetate dianion (2.6 mL of a freshly prepared 1M solution asdescribed in Example 10) was added to a solution of5,5-bis(4-fluorophenyl)-4-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2,4-pentadienal(1.1 g, 2.6 mmoles) in 15 mL of tetrahydrofuran at -40° C. Afterstirring for 2 hours, analytical TLC eluted with 25% (v/v) ethyl acetatein hexane showed starting aldehyde and therefore, another 1.2 mL ofdianion solution was added. The reaction mixture was allowed to warm to0° C. and then quenched with 1N HCl. The mixture was extracted withmethylene chloride, dried (MgSO₄) and concentrated in vacuo. The residuewas purified by column chromatography on silica gel eluting with 1%(v/v) methanol in methylene chloride to give 0.9 g of the title compoundas an oil. MS (CI): m/e=557 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.5-6.6 (9H, m), 5.43 (2H, s), 5.00 (1H, dd), 4.6(1H, m), 3.7-3.4 (6H, s over m), 3.30 (3H, s), 2.72 (2H, d), 1.22 (3H,t) ppm.

EXAMPLE 72 Ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-3-oxo-6,8-nonadienoate

Ethyl acetoacetate dianion (2.1 mL of freshly prepared 1M solution asdescribed in Example 10) was added to a solution of5,5-bis(4-fluorophenyl)-4-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2,4-pentadienal(0.9 g, 2.0 mmoles) in 15 mL of tetrahydrofuran at -50° C. Afterstirring for 1 hour, another 1 mL of dianion solution was added and themixture stirred for an additional 30 minutes. The reaction mixture wasquenched with 1N HCl and then extracted with methylene chloride. Theorganic extracts were dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel eluting with1% (v/v) methanol in methylene chloride to give 0.55 g of the titlecompound. MS (CI): m/e=557 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.30-7.05 (4H, m), 6.90-6.70 (5H, m), 5.85 (2H, s),5.35 (1H, dd), 4.70-4.53 (1H, m), 4.17 (2H, q), 3.48 (4H, m), 3.38(3H,s), 2.72 (2H, d), 1.26 (3H, t) ppm;

¹³ C NMR (CDCl₃) δ: 202.03, 190.30, 166.60, 164.88, 164.36, 164.15,159.92, 146.22, 137.49, 137.41, 135.13, 132.29, 132.13, 131.63, 131.47,131.18, 131.05, 131.02, 130.93, 128.67, 124.46, 115.45, 115.03, 114.92,114.51, 91.16, 80.80, 70.84, 69.28, 67.96, 61.37, 58.90, 49.82, 49.18,14.01 ppm.

EXAMPLE 73 Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-6,8-nonadienoate

To a solution of ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-3-oxo-6,8-nonadienoate(0.9 g, 1.6 mmoles) in tetra hydrofuran (20 mL) at -10° C. was addedtriethylborane (2.1 mL of 1M solution) and the mixture stirred for 45minutes during which time the initially yellow solution becamecolorless. The solution was cooled to -78° C. and sodium borohydride(0.13 g, 3.2 mmoles) and methanol (0.75 mL) were added. After 2 hours at-78° C., the solution was diluted with 50 mL of hexane and hydrolyzedwith 1N HCl. The aqueous layer was separated and extracted with ethylacetate. The combined organic solutions were dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in methanol (30 mL) andthe solution stirred for 40 hours. The solution was concentrated invacuo and the residue purified by column chromatography on silica gelelution with 1% (v/v) methanol in methylene chloride to give 0.4 g ofthe title compound. MS (CI): m/e=559 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.4-6.8 (8H, m), 6.65 (1H, d), 5.40 (2H, s), 4.95(1H, dd), 4.4-3.5 (8H, m), 3.30 (3H, s), 2.40 (2H, d), 1.80-1.35 (2H,m), 2.20 (3H, t) ppm.

EXAMPLE 74 Ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-6,8-nonadienoate

To a solution of ethyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-3-oxo-6,8-nonadienoate(0.9 g, 1.6 mmoles) in tetra hydrofuran (15 ml) at -0° C. was addedtriethylborane (2.1 mL of 1M solution, 2.1 mmoles) and the solutionstirred for 1.5 hours during which time the yellow color disappeared.The mixture was cooled to -75° C. and sodium borohydride (0.13 g, 3.2mmoles) and methanol (0.9 mL) were added. After stirring for 2 hours,the solution was diluted with 50 mL of hexane and hydrolyzed by additionof 1N HCl. The aqueous layer was separated and extracted with ethylacetate. The combined organic fractions were dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in methanol and thesolution stirred for 16 hours. The methanolic solution was concentratedin vacuo and the residue purified by column chromatography on silica geleluting with 1.5% (v/v) methanol in methylene chloride to give 0.6 g ofthe title compound. MS (CI): m/e=559 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.38-7.04 (4H,m), 6.92-6.65 (5H, m), 6.92 (2H, s),6.40 (1H, dd), 4.45 (1H, m), 4.15 (3H, q over m), 3.43 (4H, s), 3.32(3H, s), 2.45 (2H, d), 1.72-1.65 (2H, m), 1.25 (3H, t) ppm;

¹³ C NMR (CDCl₃) δ: 172.45, 165.05, 164.69, 164.32, 160.12, 159.40,146.06, 137.75, 137.70, 136.96, 136.13, 132.44, 132.28, 131.82, 131.66,131.40, 131.25, 131.05, 128.32, 124.91, 115.65, 115.40, 115.23, 114.92,114.69, 80.97, 72.25, 71.05, 69.48, 68.22, 60.90, 59.15, 42.53, 41.06,14.27 ppm.

EXAMPLE 75 Sodium(±)-erythro-9,9-Bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-6,8-nonadienoate

A solution of ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-6,8-nonadienoate(0.3 g, 0.54 mmole) and sodium hydroxide (0.54 mL of a 1N solution, 0.54mmole) in ethanol (15 mL) was stirred for 3 hours. The solution wasconcentrated in vacuo and the desired product was lyophilized under highvacuum to produce 250 mg of the title compound which appears to containabout two moles of water; m.p.=110°-135° C. MS (FAB): m/e=553 for (M+H)⁺;

¹ H NMR (D₂ O) δ: 7.38-7.33 (2H, m), 7.22-7.18 (2H, t), 6.98-6.89 (4H,m), 6.67 (1H, d), 5.50 (2H, s), 5.23 (1H, dd), 4.27 (1H, m), 3.93 (1H,m), 3.61-3.46 (4H, m), 3.28 (3H, s), 2.30-2.28 (2H, m), 1.68-1.50 (2H,m) ppm;

¹³ C NMR (D₂ O) δ: 181.37, 165.49, 165.02, 162.75, 162.27, 149.52,138.74, 137.38, 136.57, 133.84, 133.75, 132.97, 132.88, 129.29, 121.34,116.98, 116.73, 116.49, 78.19, 72.00, 71.02, 70.74, 68.31, 59.58, 46.05,44.11 ppm;

Anal. Calcd. for C₂₆ H₂₇ F₂ N₄ O₆ Na 2H₂ O: C, 53.06; H, 5.31; N, 9.53.Found: C, 53.36; N, 5.04; N, 9.02.

EXAMPLE 76 Sodium(±)-erythro-9,9-Bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-8,9-nonadienoate

A solution of ethyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-6,8-nonadienoate(0.45 g, 0.81 mmoles) and sodium hydroxide (0.81 mL of a 1N solution,0.81 mmoles) in ethanol (10 mL) was stirred for 30 minutes. The solutionwas concentrated in vacuo and the desired product was lyophilized underhigh vacuum to produce 350 mg of the title compound as an orange powder;m.p.=175°-190° C. MS (FAB): m/e=551 for (M-H)⁻ ;

IR (KBr) ν_(max) : 3400 (v.br), 1603, 1585, 1515 (s), 1410 (br), 1230842 (s) cm⁻¹ ;

¹ H NMR (D₂ O) δ: 7.17-7.11 (2H, m), 7.02-6.97 (2H, t), 6.81-6.58 (5H,m), 5.86 (2H, s), 5.35 (1H, dd), 4.26 (1H, m), 3.97-3.93 (1H, m),3.41-3.24 (4H, m), 3.22 (3H, s), 2.33-2.21 (2H, m), 1.67-1.48 (2H, m)ppm;

Anal. Calcd. for C₂₆ H₂₇ F₂ N₄ O₆ Na 0.5H₂ O: C, 55.62; H, 5.03; N,9.98; H₂ O, 1.60. Found: C, 55.46; H, 5.03; N, 9.79; H₂ O, 1.89.

EXAMPLE 775,5-Bis(4-fluorophenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal

To a mixture of3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (71.6g, 0.22 mole) and triphenylphosphoranylidene acetaldehyde (66.8 g, 0.22mole) was added 1.1 liters of dry benzene and the suspension was heatedto reflux temperature over a period of 30 minutes. The reaction wasallowed to proceed at reflux temperature for 2 hours. Analytical TLCeluted five times with 30% (v/v) ethyl acetate in hexanes showed onlyone major spot at R_(f) =0.37 for the desired product. The crude hotreaction mixture was diluted with an equal volume of hexane and the warmmixture was quickly filtered through a bed of activated charcoal. Thefiltrate was allowed to stand at room temperature from which 58.12 g(75.2%) of the desired product was collected. A second crystallizationfrom the filtrate yielded mostly triphenylphosphine oxide. Concentrationof the filtrate yielded an additional amount of the desired product togive a total of 71 g (91.8%) of the title compound. The combinedmaterial was recrystallized from ethyl acetate-hexane to give pure titlecompound; m.p.=164°-165° C. A ¹ H NMR of the recrystallized materialshowed no detectable double homologated product.

Anal. Calcd. for C₁₉ H₁₄ F₂ N₄ O: C, 64.77; H, 4.01; N, 15.90. Found: C,65.20; H, 4.09; N, 16.03.

EXAMPLE 78 3,3-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenalA. 1,1-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol

To a solution of 1,5-dimethyltetrazole (0.98 g, 10.0 mmoles) intetrahydrofuran (20 mL) at -30° C. was added n-butyl lithium (4.7 mL of2.14M solution, 10.0 mmoles). After stirring for 0.25 hour, the solutionwas cooled to -50° C. and 4,4'-difluorobenzophenone (1.74 g, 8.0 mmoles)was added. After stirring for 1 hour at -50° C. and 1 hour at -10° C.,the reaction was quenched with 1N hydrochloric acid. The mixture wasextracted with methylene chloride, dried and evaporated in vacuo. Theresidue was purified by column chromatography on silica gel eluting with40% (v/v) ethyl acetate in hexane to give 2.0 g of the title compound;m.p.=116°-118° C.

Anal. Calcd. for C₁₆ H₁₄ F₂ N₄ O: C, 60.76; H, 4.47; N, 17.72. Found: C,60.62; H, 4.52; N, 17.63.

B. 1,1-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (4.2 g,12.7 mmoles) [prepared in Step A] and potassium hydrogen sulfate washeated at 195° C. for 0.5 hour. After cooling, the mixture was dissolvedin chloroform and washed with water. The organic layer was dried andevaporated in vacuo. The residue was triturated with diethyl ether togive 3.9 g of the title compound; m.p.=169°-171° C.

Anal. Calcd. for C₁₆ H₁₂ F₂ N₄ : C, 64.43; H, 4.06; N, 18.88. Found: C,63.93; H, 4.00; N, 19.25.

C. 3,3-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal

To a finely divided suspension of1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (1.0 g, 3.3mmoles) [prepared in Step B] in tetrahydrofuran (10 mL) at -80° C. wasadded n-butyl lithium (1.54 mL of 2.14M solution), 3.3 mmoles) with theformation of a dark violet color. After stirring for 40 minutes at -80°C., ethyl formate (0.32 g, 4.3 mmoles) was added and the mixture stirredfor 2.5 hours at -80° C. The mixture was hydrolyzed with 1N hydrochloricacid and extracted with methylene chloride. The extracts were dried(MgSO₄) and evaporated in vacuo. The residue was triturated with diethylether to give 0.77 g of yellow solid, m.p. 128°-131° C. The solid wascrystallized from isopropyl acetate-hexane to give 0.55 g of the titlecompound; m.p.=130°-132° C.

Anal. Calcd. for C₁₇ H₁₂ F₂ N₄ O: C, 62.58; H, 3.71; N, 17.18. Found: C,62.15; H, 3.82; N, 16.75.

EXAMPLE 795,5-Bis(4-fluorophenyl)-4-(1-methyl-1H-tetrazol-5yl)-2,4-pentadienal

A solution of3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal (1.0 g,3.07 mmoles) and triphenylphosphoranylidene acetaldehyde (0.93 g, 3.07mmoles) in benzene was heated at reflux for 1 hour. The benzene wasremoved in vacuo and the residue was purified by column chromatographyon silica gel eluting with 15% (v/v) ethyl acetate in hexane to give 0.7g of the title compound; m.p.=156°-157.5° C.

Anal. Calcd. for C₁₉ H₁₄ F₂ N₄ O: C, 64.77; H, 4.01; N, 15.91. Found: C,65.13; H, 4.05; N, 15.71.

EXAMPLE 803,3-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl-2-propenal A.5-Ethyl-1-methyl-1H-tetrazole

To a slurry of 1,5-dimethyltetrazole (4.9 g, 0.05 mole) in drytetrahydrofuran (50 mL) was added 2.5M n-butyllithium in hexanes (20 mL,0.05 mole) over a period of 15 minutes at -78° C. under an inertatmosphere. This mixture was stirred for 30 minutes and a yellowishprecipitate formed during this time. Methyl iodide (3.7 mL, 0.06 mole)was then added over a period of 15 minutes. After stirring for anadditional 30 minutes, the clear reaction mixture was diluted with waterand extracted with ethyl acetate (3×50 mL). The aqueous layer was washedwith chloroform (2×25 mL), and the combined organic layer was dried oversodium sulfate and concentrated under reduced pressure to give an oil.The oil was purified by distillation to give 5.2 g (92%) of the titlecompound; b.p.=89°-90° C. at 0.05 mm Hg.

¹ H NMR (CDCl₃) δ: 4.05 (s, 3H), 2.86 (q, 2H), 1.41 (t, 3H);

¹³ C NMR (CDCl₃) δ: 156.0, 33.24, 16.75, 11.20.

B. 1,1-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propanol

To a solution of 5-ethyl-1-methyl-1H-tetrazole (5.6 g, 0.05 mole)[prepared in Step A] in 60 mL of dry tetrahydrofuran was added 2.5Mn-butyllithium (20 mL, 0.05 mole) in hexane over 5 minutes at -78° C.(bath temperature) under an inert atmosphere. The mixture was stirredfor 30 minutes and a solution of 4,4'-difluorobenzophenone (10.8 g, 0.5mole) in 25 mL of dry tetrahydrofuran was added over 5 minutes. Thismixture was stirred for an additional 2 hours while the bath temperaturewas slowly warmed to -20° C. The reaction was quenched with 1N HCl andextracted with ethyl acetate (3×50 mL) and chloroform (3×50 mL). Thecombined organic layer was dried over sodium sulfate and concentratedunder reduced pressure to give a white solid. The solid was purified bycrystallization from ethanolhexane to give 10.8 g (65%) of the titlecompound; m.p.=160°-161° C.

IR (KBr) ν_(max) : 3400 cm⁻¹ ;

¹ H NMR (CDCl₃) δ: 7.8-7.02 (m, 8H), 5.95 (s, 1H), 4.65 (q, 1H), 3.98(s, 3H), 1.29 (d, 2H).

¹³ C NMR (CDCl₃) δ: 162.57, 162.37, 159.14, 156.71, 142.48, 140.54,128.25, 128.13, 127.52, 127.42, 114.67, 114.41, 114.38, 78.56, 36.99,33.43, 14.52.

Anal. Calcd. for C₁₇ H₁₆ F₂ N₄ O: C, 61.81; H, 4.88; N, 16.96. Found: C,61.79; H, 4.90; N, 17.09.

C. 1,1-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propene

A slurry of1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)propanol (8.25 g,0.025 mole) [prepared in Step B] and 100 mg of p-toluene sulfonic acidmonohydrate in xylene (60 mL) was heated to reflux with a Dean & Starkwater collecting apparatus for a period of 12 hours. The reactionmixture was washed with 1N NaOH (10 mL) while it was warm and with water(100 mL). Concentration of the organic layer gave off-white crystals ofproduct. This was purified by recrystallization from ethanol-hexane togive 7.1 g (91%) of the title compound as white crystals; m.p.=146°-147°C.

IR (KBr) ν_(max) : 1575; 1500 cm⁻¹.

¹ H NMR (CDCl₃) δ: 7.42-6.85 (m, 8H), 3.53 (s, 3H), 2.14 (s, 3H);

¹³ C NMR (CDCl₃) δ: 163.37, 163.08, 160.13, 155.61, 144.60, 145.34,136.47, 136.42, 136.24, 136.19, 131.65, 131.54, 131.11, 131.01, 119.53,115.51, 115.27, 115.22, 33.50, 21.20.

Anal. Calcd. for C₁₇ H₁₃ F₂ N₄ : C, 65.37; H, 4.51; N, 17.94. Found: C,65.64; H, 4.61; N, 18.09.

D.3,3-Bis(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene

A slurry of1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propene (61.46g, 0.197 mole) [prepared in Step C], N-bromosuccinamide (35.06 g, 0.197mole) and catalytic amount of azobis isobutyronitrile or benzoylperoxide in carbon tetrachloride (1.2 liters) was heated to reflux in aninert atmosphere for a period of 2 hours. The reaction mixture wascooled to ambient temperature and the solid from the reaction wasfiltered. The filtrate was concentrated under reduced pressure and thesolid obtained was recrystallized from toluene-hexane to give 72 g (93%)of the title compound as white crystals; m.p.=159°-160° C.

IR (KBr) ν_(max) : 1600 cm⁻¹.

¹ H NMR (CDCl₃) δ: 7.5-7.1 (m, 8H), 4.44 (s, 2H), 3.53 (s, 3H).

¹³ C NMR (CDCl₃) δ: 163.94, 163.74, 160.60, 160.45, 143.42, 149.68,135.20, 135.15, 134.69, 131.43, 131.31, 130.90, 130.80, 119.57, 115.94,115.77, 115.65, 115.50.

Anal. Calcd. for C₁₇ H₁₄ F₂ BrN₄ : C, 52.19; H, 3.34; N, 14.32. Found:C, 52.58; H, 3.47; N, 14.49.

E. 3,3-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

To a solution of sodium ethoxide (3.93 g of sodium metal, 0.17 mole) in500 mL of absolute ethanol was added 2-nitropropane (16.66 g, 0.187mole) slowly over 5 minutes. The bromo compound prepared in the aboveStep D (67.1 g, 0.17 mole) was added portionwise over a period of 10minutes. The reaction mixture was stirred for 2 hours and the ethanolwas removed in vacuo. The residue was dissolved in CH₂ Cl₂ (500 mL),washed with water (250 mL) and dried over sodium sulfate. The organiclayer was concentrated under reduced pressure to give an oil. The oilwas dissolved in hot toluene (350 mL) and trituration with hexane (350mL) gave 50.6 g (91%) of the title compound as white crystals;m.p.=135°-137° C.

EXAMPLE 81[1,1-Bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propen-3-yl]triphenylphosphoniumbromide

A slurry of3,3-bis(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene(1.95 g, 0.005 mole) [prepared in Example 80, Step D] andtriphenylphosphine (1.3 g, 0.005 mole) in cyclohexane (25 mL) was heatedto reflux. The reaction mixture became a clear solution after 30 minutesand a white precipitate appeared after 1 hour. The mixture was heatedfor an additional 8 hours, cooled to ambient temperature and the solidwas collected by filtration and washed with diethyl ether. This whitepowder was dried in vacuum at 50° C. to give 3.0 g (92%) of the titlecompound; m.p.=254°-255° C.

IR (KBr) ν_(max) : 3450, 1600, 1500, 1425 cm⁻¹.

¹ H NMR (DMSO-d₆) δ: 7.92-6.80 (m, 23H), 4.94 (6d, 2H), 3.83 (s, 3H);

¹³ C NMR (DMSO-d₆) δ: 163.53, 163.36, 160.28, 160.87, 154.04, 153.89,152.76, 135.11, 134.79, 134.16, 133.68, 133.54, 130.53, 130.45, 130.35,130.21, 130.07, 118.02, 116.89, 116.18, 115.89, 115.62, 115.32, 111.43,111.39, 34.22, 28.88, 28.22.

Anal. Calcd. for C₃₅ H₂₈ BrF₂ N₄ P: C, 64.31; H, 4.32; N, 8.57. Found:C, 64.02; H, 4.37; N, 8.89.

EXAMPLE 82 Methyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a slurry of the phosphonium bromide (0.326 g, 0.5 mmole) [prepared inExample 81] and methylerythro-3,5-bis(diphenyl-t-butylsilyloxy)-6-oxo-hexanoate [preparedaccording to the general procedures described by P. Kapa, et al. inTetrahedron Letters, 2435-2438 (1984) and in U.S. Pat. No. 4,571,428,issued Feb. 18, 1986 to P. K. Kapa] (0.26 g, 0.4 mmole) in drydimethylformamide (1 mL) was added potassium t-butoxide (0.067 g, 0.6mmole) at -20° C. (bath temperature) in an inert atmosphere. The slurrybecame a red solution and was stirred for 18 hours at -10° C. Thereaction was worked up by adding ammonium chloride solution (10 mL) andextracting with methylene chloride (2×30 mL). The organic layer wasdried over sodium sulfate and concentrate to give an oil. The oil waspurified through a pad of silica gel and the major fraction was isolatedas an oil (160 mg). The oil (160 mg) was stirred with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 mL) and few drops ofglacial acetic acid for a period of 18 hours. The reaction mixture waspoured into water (10 mL) and extracted with ethyl acetate (3×20 mL).The organic layer was dried over sodium sulfate and concentrated togiven an oil. The oil was purified by silica gel flash columnchromatography eluting with ethyl acetate:hexane (2:1) to give 0.08 g(75%) of the title compound as an oil. MS (CI): m/e=471 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.26-6.6 (m, 9H), 5.37 (dd, 1H), 4.44 (m, 1H), 4.24(m, 1H), 3.71 (s, 3H), 3.56 (s, 3H), 2.47 (d, 2H), 1.58 (m, 2H).

A more polar fraction was also isolated (≃20 mg) and identified as thecorresponding trans lactone.

EXAMPLE 83 4,4'-Difluoro-2,2'-dimethylbenzophenone

To a well stirred mixture of aluminum chloride (6.1 g, 46.0 mmoles) incarbon tetrachloride (14 mL) at 0° C., 3-fluorotoluene (1 g from a totalof 10 g, 90.0 mmoles) was added and the mixture stirred for 10 minutes.The remainder of the 3-fluorotoluene in 9 mL of carbontetrachloride wasadded and the mixture stirred at 0° C. for 4 hours. The mixture wascooled to -20° C. and hydrolyzed by adding 25 mL 1N hydrochloric acid.The organic layer was separated and concentrated in vacuo. The residuewas stirred for 16 hours with a mixture of benzene (20 mL), water (20mL), and acetic acid (5 mL). The aqueous layer was separated andextracted with diethyl ether. The combined organic fractions were dried(MgSO₄) and concentrated in vacuo. Analytical TLC of the residue showed3 spots; R_(f) =0.67, 0.59 and 0.56 [ 5% (v/v) ethyl acetate in hexaneon silica gel]. Column chromatography on silica gel with 0.5% (v/v)ethyl acetate in hexane and collection of the appropriate fractionscontaining material having R_(f) =0.67 [5% (v/v) ethyl acetate inhexane] gave 1.3 g of the title compound; m.p.=50°-52° C. MS (CI):m/e=247 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.26 (2H, dd), 6.96 (2H, dd), 6.87 (2H, dt), 2.42(6H, s).

Anal. Calcd. for C₁₅ H₁₂ F₂ O: C, 73.17; H, 4.92. Found: C, 73.34; H,5.02.

EXAMPLE 84 2,4'-Difluoro-4,2'-dimethylbenzophenone

Concentration of the appropriate fractions from the silica gel columnchromatography of Example 83 having material with R_(f) =0.59 gave 2.4 gof the title compound; m.p.=29°-31° C. MS (CI): m/e=347 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.53 (1H, t), 7.39 (1H, dd), 7.19-6.85 (4H, m), 2.42(3H, s), 2.39 (3H, s).

Anal. Calcd. for C₁₅ H₁₂ F₂ O: C, 73.17; H, 4.92. Found: C, 73.34; H,4.86.

EXAMPLE 85 2,2'-Difluoro-4,4'-dimethylbenzophenone

Concentration of the appropriate fractions from the silica gel columnchromatography of Example 83 having material with R_(f) =0.56 andtrituration of the residue with hexane gave 1.2 g of the title compound;m.p.=84°-85.5° C.

¹ H NMR (CDCl₃) δ: 7.57 (2H, t, J_(H--H) =8 Hz, J_(FH) =8 Hz), 7.02 (2H,d, J_(H--H) =8 Hz), 6.89 (2H, d, J_(FH) =8 Hz), 2.39 (6H, s).

Anal. Calcd. for C₁₅ H₁₂ F₂ O: C, 73.17; H, 4.92. Found: C, 73.19; H,4.88.

EXAMPLE 861,1-Bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol

To a suspension of 1,5-dimethyltetrazole (3.8 g, 39.0 mmoles) intetrahydrofuran (40 mL) at -40° C. was added butyl lithium (17.7 mL of a2.2M solution, 39.0 mmoles). Aftering stirring for 10 minutes,4,4'-difluoro-2,2'-dimethylbenzophenone (8 g, 32.5 mmoles) was added andthe solution stirred for 3 hours. The reaction was quenched with 1Nhydrochloric acid. The aqueous layer was separated and extracted withethyl acetate. The combined organic phases were dried (MgSO₄) andconcentrated in vacuo to give 7.5 g of the title compound;m.p.=186°-188° C.

anal. Calcd. for C₁₈ H₁₈ F₂ N₄ O: C: 62.99; H, 5.27; N, 16.27 Found: C,63.01; H, 5.34; N, 16.18.

EXAMPLE 871,1-Bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of1,1-bis-(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol(0.5 g, 1.5 mmoles) and p-toluenesulfonic acid (0.2 g) was heated atreflux in toluene (30 mL) for 16 hours. The mixture was cooled, dilutedwith diethyl ether (50 mL) and extracted with saturated sodiumbicarbonate solution and water. The organic layer was dried (MgSO₄) andconcentrated in vacuo. The residue was triturated with diethyl ether togive 0.3 g of the title compound; m.p.=120°-125° C.

Anal. Calcd. for C₁₈ H₁₆ F₂ N₄ : C, 66.25; H, 4.95; N, 17.17. Found: C,66.55; H, 4.92; N. 16.84.

EXAMPLE 883,3-Bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

To a solution of1,1-bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene(1.6 g, 5.0 mmoles) in tetrahydrofuran at -70° C. was added butyllithium (2.3 mL of 2.2M solution, 5.0 mmoles). After stirring for 0.25hour, ethyl formate (0.44 g, 6.0 mmoles) was added and the mixturestirred for 2 hours. The reaction was quenched with 1N hydrochloric acidand the mixture was extracted with methylene chloride. The extracts weredried and concentrated in vacuo to give 1.0 g of the title compound;m.p.=135°-136° C.

Anal. Calcd. for C₁₉ H₁₆ F₂ N₄ O: C, 64.41; H, 4.56; N, 15.82. Found: C,64.22; H, 4.59; N, 15.50.

EXAMPLE 895,5-Bis(4-fluoro-2-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal

A solution of3,3-bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal(0.88 g, 2.5 mmoles) and triphenylphosphoranylidene acetaldehyde (0.75g, 2.5 mmoles) in benzene (50 mL) was heated at reflux for 3 hours. Thesolvent was removed by evaporation and the crude residue purified bycolumn chromatography on silica gel eluting with 1% (v/v) methanol inmethylene chloride. The fractions containing material having R_(f) =0.9[1:20 (v/v) methanolmethylene chloride] were combined and concentratedto give 0.8 g of the title compound; m.p.=75°-95° C. MS: M⁺ =380;

¹ H NMR (CDCl₃) δ: 9.52 (1H, d), 7.30-6.67 (7H, m), 5.82 (1H, dd), 3.62(3H, s), 2.23 (3H, s), 2.00 (3H, s).

Anal. Calcd. for C₂₁ H₁₈ F₂ N₄ O: C, 66.31; H, 4.78; N, 14.73. Found: C,65.76; H, 4.85; N, 14.52.

EXAMPLE 90 tert-Butyl9,9-bis(4-fluoro-2-methylphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate

To a solution of5,5-bis(4-fluoro-2-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal(1.0 g, 2.5 mmoles) in tetrahydrofuran at -50° C. was added the dianionof t-butyl acetoacetate (2.5 mL of a 1M solution, 2.5 mmoles) preparedby adding t-butyl acetoacetate (4.0 g, 25.0 mmoles) in tetrahydrofuran(4 mL) to a suspension of sodium hydride (1.0 g of 60% dispersion, 25.0mmoles) in tetrahydrofuran at -5° C. followed by cooling to -30° C. andthe addition of butyl lithium (11.4 mL of 2.2M solution, 25 mmoles).After stirring for 1.5 hours, analytical TLC indicated starting aldehydeand another 0.5 mL of dianion solution was added. The solution wasstirred an additional 0.5 hour and quenched with 1N hydrochloric acid.The mixture was extracted with methylene chloride. The extracts weredried and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with methanol in methylene chlorideto produce 0.6 g of the title compound; m.p.=65°-72° C.

Anal. Calcd. for C₂₉ H₃₂ F₂ N₄ O₄ : C, 64.48; H, 5.99; N, 10.41. Found:C, 64.50; H, 5.98; N. 10.16.

EXAMPLE 91 tert-Butyl(±)-erythro-9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of t-butyl9,9-bis(4-fluoro-2-methylphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate(2.5 g, 4.6 mmoles) in tetra hydrofuran (30 mL) at -5° C. was addedtriethylborane (6.0 mL of a 1M solution, 6.0 mmoles) and the solutionstirred for 1 hour. After cooling to -78° C., sodium borohydride (0.36g, 9.0 mmoles) and methanol (2 mL) were added. The mixture was stirredat -78° C. for 2 hours and diluted with hexane (15 mL). The mixture washydrolyzed with 1N hydrochloric acid. The aqueous layer was separatedand extracted with methylene chloride. The combined organic solutionswere dried and concentrated in vacuo. The residue was dissolved inmethanol and the solution stirred for 18 hours. The solution wasconcentrated in vacuo and the residue purified by column chromatographyon silica gel eluting with 1% (v/v) methanol in methylene chloride toproduce 1.7 g of the title compound as a white powder; m.p.=75°-80° C.

¹ H NMR (CDCl₃) δ: 7.15-6.60 (7H, m), 6.43 (1H, d), 5.26 (1H, dd), 4.42(1H, m), 4.18 (1H, m), 3.92 (1H, s), 3.64 (3H, s), 2.39 (2H, d), 2.26(3H, bs), 2.04 (3H, s), 1.57 (2H, m), 1.43 (9H, s);

Anal. Calcd. for C₂₉ H₃₄ F₂ N₄ O₄ : C, 64.44; H, 6.34; N, 10.37. Found(corr. for 0.28% H₂ O): C, 64.14; H, 6.41; N, 10.16.

EXAMPLE 92 Sodium(±)-erythro-9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of t-butyl9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate(1.65 g, 3.05 mmoles) in ethanol (50 mL) was added sodium hydroxide(3.05 mL of 1N solution, 3.05 mmoles) and the solution stirred at roomtemperature for 3 hours and at 50° C. for 1 hour. The solution wasconcentrated in vacuo to give 1.3 g of the title compound which appearsto contain about one mole of water; m.p.=215°-225° C. (dec.).

Anal. Calcd. for C₂₅ H₂₅ F₂ N₄ O₄ Na H₂ O: C, 57.26; H, 5.19; N, 10.69.Found: C, 57.30; H, 5.20; N, 10.00.

EXAMPLE 931,1-Bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol

To a solution of 1,5-dimethyltetrazole (4.6 g, 4.7 mmoles) intetrahydrofuran (40 mL) at -═° C. was added butyl lithium solution (21.4mL of a 2.2M solution, 4.7 mmoles). After stirring for 10 minutes, asolution of 2,2'-difluoro-4,4'-dimethylbenzophenone in tetrahydrofuran(15 mL) was added. The solution was stirred for 2.5 hours during whichtime it was allowed to warm to -10° C. The reaction was quenched byadding 1N hydrochloric acid. The layers were separated and the aqueouslayer was extracted with methylene chloride. The combined organicfractions were dried (MgSO₄) and evaporated. The residue was trituratedwith diethyl ether and crystallized from isopropyl acetate to give 8.0 gof the title compound; m.p.=150°-151° C. MS: M⁺ =344.

Anal. Calcd. for C₁₈ H₁₈ F₂ N₄ O: C, 62.79; H, 5.27; N, 16.27. Found: C,62.84; H, 5.23; N, 16.28.

EXAMPLE 941,1-Bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene

A suspension of1,1-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol(7.3 g, 21.0 mmoles) in toluene (200 mL) with p-toluene sulfonic acid (3g) and the mixture heated at reflux for 14 hours. After cooling, themixture was diluted with diethyl ether and extracted with saturatedsodium bicarbonate solution and water. The organic layer was dried(MgSO₄) and evaporated. The residue was triturated with isopropyl etherto give the title compound; m.p.=58°-60° C.

Anal. Calcd. for C₁₈ H₁₆ F₂ N₄ : C, 66.25; H, 4.95; N, 17.17. Found: C,66.27; H, 4.94; N. 16.93.

EXAMPLE 953,3-Bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal

To a solution of1,1-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene(1.6 g, 5.0 mmoles) in tetrahydrofuran (20 mL) at -78° C. was addedbutyl lithium (2.3 mL of a 2.2M solution, 5 mmoles). After stirring for15 minutes, ethyl formate (0.44 g, 6.0 mmoles) was added and thesolution stirred with cooling for 2 hours. The reaction was quenchedwith 1N hydrochloric acid and the mixture extracted with diethyl ether.The extracts were dried (MgSO₄) and evaporated. The residue wascrystallized from isopropyl acetate to give 0.66 g of the titlecompound; m.p.=154°-155° C.

Anal. Calcd. for C₁₉ H₁₆ F₂ N₄ O: C, 64.41; H, 4.56; N, 15.82; Found: C,64.44; H, 4.63; N, 15.58.

EXAMPLE 965,5-Bis(2-fluoro-4-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal

A solution of3,3-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal(1.35 g, 3.8 mmoles) and triphenylphosphoranylidene acetaldehyde (1.16g, 3.8 mmoles) in benzene was heated at reflux for 3 hours. The solventwas removed and the residue purified by column chromatography on silicagel eluting with 1% (v/v) methanol in methylene chloride. The fractionscontaining material having R_(f) =0.9 [methanol-methylene chloride; 1:20(v/v)] were combined and concentrated to give 1.3 g of the titlecompound; m.p.=88°-108° C.

Anal. Calcd. for C₂₁ H₁₈ F₂ N₄ O: C, 66.31; H, 4.78; N, 14.73. Found: C,66.34; H, 4.96; N, 14.37.

EXAMPLE 97 tert-Butyl9,9-bis(2-fluoro-4-methylphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate

To a solution of5,5-bis(2-fluoro-4-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal(1.3 g, 3.4 mmoles) in tetrahydrofuran (15 mL) at -50 ° C. was added thedianion of t-butyl acetoacetate (3.4 mL of a 1M solution, 3.4 mmoles).After stirring for 2 hours, another 0.7 mL of dianion solution was addedand the solution stirred for an additional hour. The reaction wasquenched with 1N hydrochloric acid and the mixture extracted withmethylene chloride. The extracts were dried (MgSO₄) and concentrated.The residue was purified by column chromatography on silica gel elutingwith 1% (v/v) methanol in methylene chloride to give 1.3 g of the titlecompound; m.p.=55°-63° C.

¹ H NMR (CDCl₃) δ: 7.05-6.53 (7H, m); 5.28 (1H, dd), 4.60 (1H, m), 3.75(3H,s), 3.35 (2H, s), 3.05 (1H, bs), 2.69 (2H, d), 2.39 (3H, s), 2.33(3H, s), 1.45 (9H, s).

Anal. Calcd. for C₂₉ H₃₂ F₂ N₄ O₄ : C, 64.68; H, 5.99; N. 10.41. Found(corr. for 0.21% H₂ O): C, 64.33, H, 6.07; N, 10.21.

EXAMPLE 98 t-Butyl(±)-erythro-9,9-bis(2-fluoro-4-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of t-butyl9,9-bis(2-fluoro-4-methylphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate(1.3 g, 2.4 mmoles) in tetra hydrofuran at -5° C. was addedtriethylborane (3.1 mL of 1M solution, 3.1 mmoles). After stirring at-5° C. for 1 hour, the solution was cooled to -75° C. and sodiumborohydride (0.2 g, 4.8 mmoles) and methanol (1 mL) were added. Afterstirring at -75° C. for 2 hours, the mixture was diluted with 10 mL ofhexane and hydrolyzed with excess 1N hydrochloric acid. The aqueouslayer was separated and extracted with methylene chloride. The combinedorganic solutions were dried (MgSO₄) and concentrated in vacuo. Theresidue was dissolved in methanol and the solution stirred at roomtemperature for 19 hours. The solution was concentrated in vacuo to give0.6 g of the title compound as a white powder; m.p.=73°-77° C.

Anal. Calcd. for C₂₉ H₃₄ F₂ N₄ O₄ : C, 64.44; H, 6.34; N, 10.37. Found:C, 64.07; H, 6.45; N, 9.87.

EXAMPLE 99 Sodium(±)-erythro-9,9-bis(2-fluoro-4-methylphenyl)-3,5-dihydroxy-8-(1methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of t-butyl9,9-bis(2-fluoro-4-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate(0.6 g, 1.1 mmoles) in ethanol (20 mL) was added sodium hydroxide (1.1mL of 1N solution, 1.1 mmoles) and the solution stirred at roomtemperature for 3 hours and at 50° C. for 1 hour. The solution wasconcentrated in vacuo to produce 0.44 g of the title compound whichappears to contain about one mole of water; m.p.=200°-205° C. (dec.).

Anal. Calcd. for C₂₅ H₂₅ F₂ N₄ O₂ Na H₂ O: C, 57.26; H, 5.19; N, 10.69.Found: C, 57.00; H, 5.27; N, 10.05.

EXAMPLE 100 Sodium(3R,5S)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)nona-6,8-dienoateA. (1S)-2-Hydroxy-1,2,2-triphenylethyl(3S)-7,7-bis(4-fluorophenyl)-3-hydroxy-6-(1-methyl-1H-tetrazol-5-yl)hepta-4,6-dionate

A solution of diisopropylamine (5.33 mL; 3.85 g; 38.1 mmole) in drytetrahydrofuran (40 mL) was cooled to 0° C. and treated with buyllithium(15.2 mL of 2.5M solution in hexane; 38 mmole) and the mixture allowedto warm up to 23° C. over 15 minutes. This solution was cooled to -78°C. and added to a suspension of (S)-(-)-1,2,2-triphenyl-2-hydroxyethylacetate (5.07 g; 19.2 mmole) [prepared according to the proceduredescribed in Tetrahedron Letters, 5031-5034 (1984)] in drytetrahydrofuran (40 mL) at -78° C. The mixture was allowed to warm up to0° C. over 15 minutes. The resulting orange solution was cooled to -78°C. and treated with a solution of5,5-bis(4-fluorophenyl)-4-(1-methyl-1Htetrazol-5-yl)-2,4-pentadienal (8g; 22.73 mmole) in dry tetrahydrofuran (30 mL). After stirring at -78°C. for 20 minutes, the reaction was quenched with 2N HCl (80 mL) and thesolvent removed by evaporation. The residue was extracted with ethylacetate (3×50 mL) and the combined organic layers were dried (MgSO₄) andevaporated in vacuo. The residue was purified by silica gel columnchromatography using 30% (v/v) ethyl acetate-hexane as eluent to afford9.4 g (90% based on chiral acetate) of the title compound. [α]_(D)=-41.1° (c=1.16; CH₂ Cl₂).

¹ H NMR (DMSO-d₆) δ: 7.45-6.80 (m, 23H), 6.54 (s, 1H), 6.50 (d, J=16.0Hz, 1H), 6.05 (s, 1H), 5.15 (dd, J=15.6 Hz, J'=5.2 Hz, 1H), 5.02 (d,J=5.3 Hz, 1H), 4.33 (m, 1H), 3.70 (s, 0.3H minor diastereoisomer), 3.65(s, 2.7H major diastereoisomer), 2.29 (m, 2H).

¹³ C NMR (DMSO-d₆) δ: 194.01, 170.16, 169.32, 163.64, 163.16, 160.36,159.90, 153.00, 147.77, 145.95, 145.09, 144.50, 138.00, 136.88, 136.42,135.40, 133.04, 132.28, 131.76, 131.00, 128.54, 127.38, 127.05, 126.61,126.44, 125.74, 121.40, 115.94, 115.60, 115.40, 115.06, 78.74, 78.36,67.50 (minor diastereomer), 66.75 (major diastereomer), 59.67, 41.97,33.47, 20.68, 14.01.

B. Methyl(3S)-7,7-bis(4-fluorophenyl)-3-hydroxy-6-(1-methyl-1H-tetrazol-5-yl)hepta-4,6-dienoate

A solution of the triphenyl ester prepared in Step A (9.4 g; 13.74mmole) in dry methanol (40 mL) was added to a solution of sodium metal(2.1 g, 91 mmole) in dry methanol (300 mL) and the resulting mixturestirred at 23° C. for 30 minutes. The reaction was quenched with 2N HCl(100 mL) and the solvent removed by evaporation. The residue was dilutedwith water (100 mL) and extracted with ethyl acetate (3×70 mL). Thecombined organic layers were dried (MgSO₄) and evaporated. The residuewas purified by silica gel column chromatography using 40% (v/v) ethylacetate-hexane as eluent to afford 4.08 g (70%) of the title compound.[α]_(D) =+28.94° (c=0.85; CH₂ Cl₂).

IR (Film) ν_(max) : 3400 (br), 1735, 1500, 1220 cm⁻¹.

¹ H NMR (CDCl₃) δ: 7.30-6.60 (m, 8H), 6.725 (dd, J=15.8 Hz, J'=1.4 Hz,1H), 6.34 (dd, J=15.9Hz, J'=5.6 Hz, 1H), 4.56 (br s, 1H), 3.69 (s, 3H),3.60 (s, 3H), 3.14 (br s, 1H), 2.50 (m, 2H).

¹³ C NMR (CDCl₃) δ: 172.27, 164.61, 164.20, 161.29, 160.88, 153.43,147.46, 136.04, 135.26, 132.38, 132.26, 131.48, 131.37, 128.01, 120.96,115.91, 115.56, 68.17, 51.85, 40.84, 33.57.

C. tert-Butyl(5S)-9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-nona-6,8-dienoate

A solution of diisopropylamine (2.77 mL; 2 g; 19.8 mmole) in drytetrahydrofuran (15 mL) was cooled to 0° C. and treated withbutyllithium (8.1 mL of 2.5M solution in hexane; 20.25 mmole) and theresulting mixture allowed to warm up to 23° C. over 15 minutes. Thesolution was cooled to 0° C. and t-butylacetate (2.55 mL; 2.2 g; 18.9mmole) was added and the solution stirred at 0° C. for 15 minutes,cooled to -78° C., then added to a solution of the methyl ester preparedin Step B (2 g; 4.69 mmole) in dry tetrahydrofuran (20 mL) at -78° C.The resulting solution was allowed to warm up to 23° C. over 30 minutesand quenched with 2N HCl (20 mL). The solvent was removed by evaporationunder reduced pressure and the residue diluted with water (30 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layers weredried (MgSO₄) and evaporated in vacuo and the residue purified by silicagel column chromatography using 35% (v/v) ethyl acetate-hexane as eluentto afford 1.858 g (78%) of the title compound. [α]_(D) ²⁵ =+19.44°(c=1.08; CH₂ Cl₂).

IR (Film) ν_(max) : 3400 (br), 1735, 1710, 1595, 1510, 1220, 1155 cm⁻¹.

¹ H NMR (CDCl₃) δ: 7.30-6.80 (m, 8H), 6.72 (dd, J=15.6 Hz, J'=0.9 Hz,1H), 5.30 (dd, J=15.6 Hz, J'=5.5 Hz, 1H), 4.61 (br, 1H), 3.56 (s, 3H),3.35 (s, 2H), 2.70 (m, 2H), 1.45 (s, 9H).

¹³ C NMR (CDCl₃) δ: 202.88, 168.05, 164.61, 164.16, 161.29, 160.85,153.50, 147.30, 136.01, 132.40, 132.29, 131.51, 131.39, 127.88, 121.00,115.88, 115.83, 115.60, 115.54, 82.35, 67.85, 51.10, 49.10, 33.59,27.99.

D. tert-Butyl(3R,5S)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)nona-6,8-dienoate

A solution of the β-ketoester prepared in Step C (1.85 g; 3.62 mmole) indry tetrahydrofuran (30 mL) was treated with triethylborane (3.9 mL of1M solution in THF; 3.9 mmole) and the mixture was stirred at 23° C. for1 hour while dry air was bubbled through the solution. Methanol (600 l)was added and the mixture cooled to -78° C. and treated with sodiumborohydride (320 mg; 8.42 mmole) and the mixture stirred at -78° C. for20 minutes. The reaction was quenched with 2N HCl (20 mL) and thesolvent removed by evaporation. The residue was diluted with water (30mL) and extracted with ethyl acetate (3×20 mL). The combined organicextracts were dried (MgSO₄) and evaporated and the residue dissolved inmethanol (30 mL) and stood at 23° C. for 3 hours. The solvent wasremoved by evaporation in vacuo and the residue purified by silica gelcolumn chromatography using 40% (v/v) ethyl acetate-hexane as eluent toafford 962 mg (52%) of the title compound.

¹ H NMR (CDCl₃) δ: 7.30-6.80 (8H, m), 6.71 (d, J=15.6 Hz, 1H), 5.34 (dd,J=15.6Hz, J'=7 Hz, 1H), 4.43 (br s, 1H), 4.15 (br s, 1H), 3.95 (m, 2H),3.58 (s, 3H), 2.36 (d, J=6.1 Hz, 2H), 1.6 (m, 2H), 1.45 (s, 9H).

¹³ C NMR (CDCl₃) δ: 172.00, 164.52, 164.12, 153.57, 146.79, 137.98,132.38, 132.26, 131.46, 131.35, 127.00, 121.25, 115.85, 115.80, 115.57,115.51, 81.66, 71.88, 68.54, 42.34, 42.36, 33.59, 28.10.

E. Sodium (3R,5S)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy8-(1-methyl-1H-tetrazol-5-yl)nona-6,8-dienoate

A solution of the dihydroxyester prepared in Step D (35 mg; 0.068 mmole)in ethanol (2 mL) was treated with 1N NaOH solution (68 l; 0.068 mmole)and the mixture stirred for 30 minutes at 23° C. The solvent was removedby evaporation in vacuo and the residue dissolved in water (2 mL) andlyophilized to afford 36 mg (100%) of the title compound; m.p.>110° C.decomp. [α]_(D) ²⁵ =-22.2° (c=0.32, H₂ O). The ¹ H NMR and ¹³ C NMR areidentical to the (±)-erythro product prepared in Example 12.

EXAMPLE 101 Ethyl 1-Methyl-5-tetrazolylacetate

To a solution of 1,5-dimethyltetrazole (10 g) in 100 mL of drytetrahydrofuran and 20 mL of hexamethylphosphoramide at -78° C. (dryice-acetone) under an argon atmosphere was added dropwise 50 mL (1.2equivalent) of n-butyllithium (2.5M in hexane). The deprotonation of1,5-dimethyltetrazole was allowed to proceed at -78° C. for 40 minutes,then at -20° C. to 30 minutes. The anion solution was rechilled at -78°C. and transferred via a cannula over a period of 45 minutes into a cold(-78° C.) solution containing 12 mL of ethyl chloroformate in 50 mL oftetrahydrofuran. The reaction mixture was diluted with aqueous 2N HCland saturated aqueous solution of sodium chloride and then extractedwith ethyl acetate. The residue from the organic extract was purified bysilica gel flash chromatography. The appropriate fractions were combinedand evaporated to give 4 g of product. The product was further purifiedby crystallization from ethyl acetate-hexanes to yield 3.52 g (21%) ofthe title compound; m.p.=64°-66° C.

Anal. Calcd. for C₆ H₁₀ N₄ O₂ : C, 42.35; H, 5.92; N, 32.92. Found: C,42.40; H, 5.98; N, 33.15.

EXAMPLE 102 Ethyl3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenoate

A mixture of titanium tetrachloride (2 mL) and carbon tetrachloride (2mL) was added to 15 mL of tetrahydrofuran at -78° C. under an argonatmosphere. The suspension was stirred at -78° C. for 30 minutes before0.2 g of 4,4'-difluorobenzophenone was added. After stirring for anadditional 30 minutes, a solution of 0.15 g of ethyl1-methyl-5-tetrazolylacetate in 1 mL of dry pyridine was added dropwise.The dark brownish suspension was stirred at -78° C. for 15 minutes, thenwas allowed to warm to 0° C. forming a thick paste. The mixture wasallowed to stand for 24 hours at ambient temperature before it waspoured into water. The aqueous mixture was extracted with ethyl acetateto yield crude product. Analytical TLC eluted five times with 20% (v/v)ethyl acetate in hexanes showed the desired product at R_(f) =0.3.Pruification by preparative chromatography on two 20×20 cm.sup. 2 0.25mm TLC plates eluted twice with 20% (v/v) ethyl acetate in hexanes togive the title compound which was identical to the compound of Example3, Step A.

EXAMPLE 103Erythro-9,9-bis(fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid hydrate A.5,5-Bis(4-fluorophenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal

A mixture of 448 g (1.37 mol) of3,3-bis(4-flurophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal and 445g (1.46 mol) of triphenylphosphoranylidene acetaldehyde in 5.5 L oftoluene was heated with stirring to 55° C. After turning off the heatsource, the temperature rose to 62° C. After 20 minutes, heat wasapplied and 60° C. was maintained for 30 minutes. Analytical TLCindicated that the reaction was complete (50% ethyl acetate in hexane).Lithium bromide (128 g, 1.47 mol) was added and the mixture was stirredat 60° C. for 1 hour. The reaction mixture was filtered and the filtratewas concentrated under reduced pressure. The residue was dissolved in900 mL of boiling absolute ethanol. To this solution was slowly added900 mL of hexane. After 16 hours at ambient temperature and 2 hours atcold freezer temperature, the mixture was filtered to give 418 g (86.6%)of the title compound; m.p.=161°-165° C.

Anal. Calcd. for C₁₉ H₁₄ N₄ F₂ O: C, 64.77; H, 4.00; N, 15.90 Found: C,64.94; H, 3.97; N, 15.82.

B. tert-Butyl9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxo-6,8-nonadienoate

A solution of 144 g (0.91 mol) of t-butyl acetoacetate in 400 mL oftetrahydrofuran was added dropwise over 1.5 hours to a mixture of 44.0 g(1.10 mol) of sodium hydride (60% in mineral oil) in 100 mL of hexaneand 500 mL of tetrahydrofuran under nitrogen at 0° C. After theaddition, this mixture was stirred for 2.3 hours. A solution 2.5Mn-butyllithium in hexane (360 mL, 0.91 mol) was added dropwise over 1hour. After stirring at 0° C. for 1 hour, 200 g (0.57 mol) of thealdehyde prepared in Step A was added all at once and the temperaturerose to 20° C. After stirring for 1 hour in an ice-water bath, 1200 mLof 10% aqueous hydrochloric acid was added over 1 hour. The organiclayer was washed with 2×300 mL of water, 300 mL of saturated sodiumchloride solution, dried with anhydrous magnesium sulfate and filtered.The filtrate was evaporated under reduced pressure to give the titlecompound which was used without further purification.

C. tert-Butylerythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

The product of Step B was dissolved in 1 L of tetrahydrofuran and 908 mL(0.908 mol) of 1.0M triethylborane in tetrahydrofuran was added over 45minutes. Air was bubbled into the solution for 5 minutes creating alighter colored solution. The resulting solution was stirred for 2 hoursat room temperature. The mixture was cooled to -74° C. and 4.0 g ofsodium borohydride was added. After 15 minutes, an additional 32.0 g(36.0 g total, 0.951 mol) of sodium borohydride was added. Afterstirring for 1 hour, 540 mL of methanol was carefully added over 1.5hours. The reaction mixture was diluted with 540 mL of 10% aqueoushydrohloric acid and then stirred at room temperature for 16 hours.Water (200 mL) was added, and the organic solvent was removed underreduced pressure. The aqueous mixture was extracted with 2×500 mL ofmethylene chloride, combined and washed with 2×400 mL of water. Theorganic layer was evaporated under reduced pressure to give the titlecompound which was used without further purification.

D.Erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid hydrate

The product of Step C was dissolved in 1 L of 95% ethanol, treated with1 L of 1N aqueous sodium hydroxide solution and stirred at roomtemperature for 60 hours. This was diluted with 2 L of water then washedwith 2×800 mL of hexane and 5×800 mL of diethyl ether. To the stirredaqueous layer was added dropwise 1.04 L of 1N hydrochloric acid over aperiod of 4 hours. The mixture was filtered, washed with water and driedto give 245 g (91%) of the title compound as a monohydrate;m.p.=111°-120° C. (dec.).

Anal. Calcd. for C₂₃ H₂₂ F₂ N₄ O₄.H₂ O C, 58.22; H, 5.10; N, 11.81; H₂0, 3.80 Found: C, 59.28; H, 5.12; N, 11.53; H₂ O, 3.02.

A sample was recrystallized from 50% aqueous methanol. The solution at74° C. was cooled slowly and seeded. After stirring at ambienttemperature for 16 hours, the solid was collected by filtration, washedwith 50% aqueous methanol and air dried to give the title compound;m.p.=107°-115° C. This product was recrystallized from 90% aqueous ethylacetate. The solution at reflux temperature was slowly cooled and seededat 50° C. After stirring at ambient temperature for 16 hours, the solidwas collected, washed with cold aqueous ethyl acetate and air dried togive the title compound; m.p.=122°-128° C. (dec.).

EXAMPLE 104 Potassium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a hot solution oferythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid hydrate (20.0 g, 42 mmol) in 200 mL of 2-propanol was added 3.0 gof potassium hydroxide in 50 mL of 2-propanol. The mixture wasevaporated under reduced pressure and the residue was dissolved in 100mL of 2-propanol, cooled and the solvent decanted. The residue was thendissolved in 100 mL of 2-propanol, heated to reflux temperature andstirred as the solution gradually cooled to ambient temperature. After 3hours, the solid was collected by filtration, washed with 2-propanol anddried in vacuo at 50° C. The product was pulverized and dried at 82° C.under high vacuum for 16 hours to give 10.5 g of the title compound;m.p.=131°-145° C. (softens at 127° C.).

Anal. Calcd. for C₂₃ H₂₁ N₄ O₄ F₂ K.0.3H₂ O: C, 55.26; H, 4.36; N,11.21; H₂ O, 1.08 Found: C, 55.44; H, 4.47; N, 11.05; H₂ O, 1.38.

EXAMPLE 105Trans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one

Method A. A mixture of 308 g (0.649 mol) of acid prepared in Example 103and 149 g (0.724 mol) of dicyclohexylcarbodiimide in 6.2 L of ethylacetate was stirred at room temperature. After 6 hours, the mixture wasfiltered and the solvent removed under reduced pressure. This residue in500 mL of toluene was combined with a similar residue in 500 mL oftoluene prepared from a second experiment using 310 g of the acidprepared in Example 103 and 148 g of dicyclohexylcarbodiimide. Thecombined solution was diluted with 1 L of toluene and warmed to 60° C.After stirring the seeded mixture for 5.5 hours, the solid was collectedby filtration, washed with 300 mL of toluene and air dried to give 446 g(78.2%) of the title compound; m.p.=146°-148° C.

Anal. Calcd. for C₂₃ H₂₀ F₂ N₄ O₃ : C, 63.01; H, 4.60; N, 12.78 Found:C, 62.93; H, 4.81; N, 12.78.

Method B. A mixture of 4.3 g of acid prepared in Example 103 in 40 mL oftoluene was heated to reflux and the water which was produced wasremoved using a Dean-Stark trap. After 5 hours, the product wascollected by filtration, washed with toluene and air dried to give 3.5 gof the title compound; m.p.=151°-154° C.

Anal. Calcd. for C₂₃ H₂₀ F₂ N₄ O₃ : C, 63.01; H, 4.60; N, 12.78 Found:C, 62.78; H, 4.64; N, 12.72.

EXAMPLE 106 Ethyl3,3-bis(4-fluorophenyl)-2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-2-propenoate

To a suspension of 0.64 g (16 mmol) 50% sodium hydride in 7.5 mL of drydimethylformamide was added 5.7 g (16 mmol) of ethyl3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate and theresultant mixture stirred for 30 minutes. To the resultant solution, 5.7g (18 mmol) bromotriphenylmethane was added and the mixture stirred for24 hours. The mixture was diluted to 200 mL with water and the insolublecollected by filtration. The product was recrystallized from ethylacetate to give 6.1 g of the title compound; m.p.=161°-162° C. (dec).

Anal. Calcd. for C₃₇ H₂₈ F₂ N₄ O₂ : C, 74.24; H, 4.72; N, 9.36 Found: C,74.31; H, 4.74; N, 9.63

EXAMPLE 1073,3-Bis(4-fluorophenyl)-2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-2-propenol

To a stirred solution of 3 g (5 mmol) ethyl3,3-bis(4-fluorophenyl)-2-[2-triphenylmethyl-2H-tetrazol-5-yl]-2-propenoatein 50 mL of methylene chloride at -70° C., 10 mL (15 mmol)diisobutylaluminium hydride solution (1.5M in methylene chloride) wasadded and the solution stirred for 3 hours. The reaction was quenchedwith water and the mixture extracted with methylene chloride. Thecombined organic fractions were dried with magnesium sulfate andconcentrated in vacuo to give 2.1 g of the title compound;m.p.=176°-178° C.

Anal. Calcd. for C₃₅ H₂₆ F₂ N₄ O: C, 75.53; H, 4.71; N, 10.07 Found: C,75.75; H, 4.57; N, 10.22

EXAMPLE 1083,3-Bis(4-fluorophenyl)-2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-2-propenal

To a solution of 2.2 g (4.0 mmol)3,3-bis(4-fluorophenyl)-2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-2-propenolin 100 mL methylene chloride was added 7 g of activated manganesedioxide. After stirring the resultant mixture for 20 hours, theinsolubles were removed by filtration and the filtrate concentrated invacuo to give a quantative yield of the title compound; m.p.=208° C.(dec).

Anal. Calcd. for C₃₅ H₂₄ F₂ N₄ O: C, 75.81; H, 4.37; N, 10.11 Found: C,73.56; H, 4.44; N, 9.54.

EXAMPLE 1095,5-Bis(4-fluorophenyl)-4-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-2,4-pentadienal

To a solution of 1.75 g (3.15 mmol)3,3-bis(4-fluorophenyl)-2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-2-propenalin 50 mL of dry benzene was added 0.96 g (3.15 mmol)triphenylphosphoranylidene acetaldehyde and the solution heated atreflux for 96 hours. The solution was concentrated in vacuo and theresidue purified by chromatography on alumina (Alcoa Chemicals, gradeF-20) eluting with 10% ethyl acetate in hexane to give uponconcentration of the appropriate fractions 0.95 g of the title compound;m.p.=122°-124° C.

Anal. Calcd. for C₃₇ H₂₆ F₂ N₄ O: C, 76.54; H, 4.52; N, 9.65 Found: C,75.84; H, 4.86; N, 9.46

EXAMPLE 110 tert-Butyl9,9-bis(4-fluorophenyl)-5-hydroxy-3-oxo-8-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-6,8-nonadienoate

A solution of the dianion of tert-butyl acetoacetate (1.2 mL of a 0.5Msolution, 0.6 mmol) prepared as described in Example 90, was added to asolution of5,5-bis(4-fluorophenyl)-4-[2-(triphenylmethyl-2H-tetrazol-5-yl]-2,4-pentadienalin tetrahydrofuran at -70° C. After stirring for 2.5 hours at -70° C.,the reaction was quenched with a saturated solution of ammoniumchloride. The mixture was extracted with diethyl ether, the ethersolution dired (MgSO₄) and concentrated in vacuo to give the titlecompound as an oil which was used without purification. MS: m/e=738 for(M⁺).

EXAMPLE 111 Disodium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1H-tetrazol-5-yl)-6,8-nonadienoateA. tert-Butyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-6,8-nonadienoate.

To a solution of tert-butyl9,9-bis(4-fluorophenyl)-5-hydroxy-3-oxo-8-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-6,8-nonadienoate(2.8 g, 3.8 mmol) in tetrahydrofuran at 0° C. was added triethylborane(3.8 mL, 1M solution) in tetrahydrofuran. After stirring for 0.5 hours,the solution was cooled to -70° C. and sodium borohydride (0.4 g, 10mmol) and methanol (2 mL) were added. After stirring for 3 hours at -70°C., the reaction was quenched with water and the mixture extracted withdiethyl ether. The extracts were dried over MgSO₄ and concentrated invacuo. The residual gum was dissolved in 100 mL of methanol and thesolution stirred at room temperature overnight. The methanol solutionwas concentrated in vacuo to give 3.0 g of title compound as a gum whichwas used in the next step without further purification.

B. tert-Butyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1H-tetrazol-5-yl)-6,8-nonadienoate

A solution of the compound prepared in Step A (0.8 g, 1.08 mmol) in 50mL methanol was acidified with 3 mL 1N hydrochloric acid. After stirringat room temperature for 2 hours, the solution was concentrated in vacuo.The residue was washed several times with hexane and the residue driedin vacuo to give 0.5 g of the title compound as a gummy solid which wasused in the next step without further purification.

C. Disodium(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1H-tetrazol-5-yl)-6,8-nonadienoate

The product from Step B was dissolved in 50 mL of ethanol and 2 mL (2mmol) 1N sodium hydroxide solution was added. After stirring at roomtemperature for 16 hours, the solution was concentrated in vacuo. Theresidue was dissolved in water and extracted with diethyl ether. Theaqueous solution was concentrated in vacuo to give 0.45 g of the titlecompound as a dry powder; m.p.=100°-105° C.

EXAMPLE 112 Dimethyl[3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propen-1-yl]phosphonate

A slurry of3,3-bis-(4-fluorophenyl)-1-bromo-2-(1-methyl-1H-tetrazol-5-yl)-2-propene(1.17 g, 3.0 mmol) and trimethyl phosphite (0.41 g, 3.3 mmol) was heatedat 100° C. for 5 minutes. After cooling to ambient temperature, excesstrimethylphosphite was removed in vacuo to give a light yellow solid.This solid was recrystallized from ethylacetate/hexane mixture to givethe title compound as a pure white solid; m.p.=140°-141° C.

IR (KBr) ν_(max) : 1604, 1511 cm⁻¹ ;

¹ H NMR (CDCl₃) δ: 7.7-6.8 (8H, m), 3.6 (3H, s), 3.5 (3H, s), 3.42 (3H,s), 3.2 (2H, d);

Anal. Calcd. for C₁₉ H₁₉ F₂ O₃ N₄ P: C, 54.29; H, 4.56; N, 13.33 Found:C, 53.83; H, 4.48; N, 13.50.

EXAMPLE 113 Methyl(±)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate

To a solution of the phosphonate (0.84 g, 2.0 mmol) [prepared in Example112] was added one equivalent of n-BuLi (2.0 mmol) at -78° C. (dryice/acetone) and the resulting deep red-colored solution was stirred at-78° C. for 15 minutes. Methyl erythro -3,5-bis(diphenyl-t-butylsilyloxy)-6-oxo-hexanoate [prepared according to thegeneral procedures described by P. Kapa, et al., in Tetrahydron Letters,2435.2438 (1984) and in U.S. Pat. No. 4,571,428, issued Feb. 18, 1986 toP. Kapa] (1.30 g, 2.0 mmol) in THF (2 mL) was added and the mixturestirred for 24 hours. The reaction mixture was allowed to warm to roomtemperature during the course of this time. The reaction was quenched byadding 5 mL) of NH₄ Cl and then extracted with ethyl acetate (2×20 mL).The organic layer was dried (Na₂ SO₄) and evaporated under reducedpressure to a yellow oil. The oil was stirred with 1M-tetra-n-butylammonium fluoride solution in tetrahydrofuran (4 mL) containing a fewdrops of glacial acetic acid for a period of 24 hours. The reactionmixture was poured into water (20 mL) and extracted with methylenechloride (3×20 mL). The organic layer was dried (Na₂ SO₄), concentrated,and the oil was purified by silica gel flash column chromatographyeluting with ethyl acetate: hexane (2:1) to give 0.284 g (41%) of thetitle compound as an oil. MS (CI): m/e=471 for (M+H)⁺ ;

¹ H NMR (CDCl₃) δ: 7.26-6.6 (9H, m), 5.29 (1H, dd), 4.42 (1H, m), 4.28(1H, m), 3.69 (3H, s), 3.54 (3H, s), 2.42 (2H, d), 1.5 (2H, m).

EXAMPLE 1141-(4-Fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-phenylethanol

A solution of 1,5-dimethyltetrazole (29.25 g; 0.298 mole) in dry THF(400 mL) was cooled to -78° C. and treated with n-butyllithium (133 mLof a 2.5M solution in hexane; 0.3325 mole) over 30 minutes. The mixturewas stirred at -78° C. for 30 minutes and treated with4-fluorobenzophenone (50 g; 0.25 mole). The mixture was stirred at -78°C. for 30 minutes and allowed to warm up to 23° C. over 2 hours. Thereaction was quenched with 2N HCl (100 mL) and the organic solvent wasremoved by evaporation. The residue was extracted with CHCl₃ (2×100 mL)and the combined organic layers were dried (Na₂ SO₄) and evaporated toafford a brown oil. Purification by chromatography using 20%EtOAc-hexane as eluent afforded the title compound as a white solid(46.3 g; 62%). m.p.=113°-114° C. (crystallized from EtOAc-hexane). MS(CI): m/e=299 for (M+H)⁺ ;

IR (KBr) ν_(max) : 3300 (br), 1605, 1510 cm⁻¹ ;

¹ H NMR δ: 7.34-7.15 (m, 7H), 6.93 (m, 2H), 4.93 (s, 1H), 3.73 (s, 2H),3.67 (s, 3H) ppm;

¹³ C NMR δ: 163.57, 160.29, 152.28, 144.94, 141.12, 141.08, 128.43,127.87, 127.75, 127.67, 125.76, 115.25, 114.96, 77.03, 35.82, 33.45 ppm;

Anal. Calcd. for C₁₆ H₁₅ FN₄ O: C, 64.42; H, 5.07; N, 18.79 Found: C,64.32; H, 5.05; N, 18.84

EXAMPLE 115(E)-1-(4-Fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-phenyletheneand(Z)-1-(4-Fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-phenylethene

A mixture of the tetrazolylethanol (3.2 g; 10.74 mmole) (prepared inExample 114) and potassium hydrogen sulfate (800 mg) was heated at 195°C. for 30 minutes. After cooling to 100° C., chloroform (30 mL) wasadded and the mixture triturated until most of the solid had dissolved.The insoluble inorganic material was removed by filtration and thesolvent removed by evaporation to afford a mixture of the titlecompounds as a light brown solid (2.8 g; 93%). Crystallized fromEtOAc-hexane. MS (CI); m/e=281 for (M+H)⁺ ;

IR (KBr) ν_(max) : 1640, 1600, 1510, 1445, 1220 cm⁻¹ ;

¹ H NMR δ: 7.50-6.90 (m, 9H), 6.75 (s, 1H), 3.60 (s, 1.7H), 3.43 (s,1.3H) ppm;

¹³ C NMR δ: 165.19, 164.58, 161.26, 153.14, 152.97, 152.22, 152.13,140.53, 137.81, 136.71, 133.99, 133.94, 131.74, 131.62, 130.38, 129.67,129.29, 128.85, 128.65, 128.38, 115.97, 115.74, 115.66, 115.45, 108.29,108.15, 33.70 ppm;

Anal. Calcd. for C₁₆ H₁₃ FN₄ : C, 68.56; H, 4.68; N, 19.99 Found: C,68.63; H, 4.77; N, 20.37

EXAMPLE 116(E)-3-(4-Fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-3-phenylpropenaland(Z)-3-(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-3-phenylpropenal

A suspension of the olefin (20 g; 71.43 mmole) (prepared in Example 115)in dry THF (200 mL) was cooled to -78° C. and treated withn-butyllithium (31.5 mL of 2.5M solution in hexane; 78.75 mmole) and theresulting mixture stirred at -78° C. for 30 minutes. Ethyl formate (6.9g; 93 mmole) was added and the mixture stirred at -78° C. for 2 hoursand allowed to warm up to 23° C. over 1 hour. The reaction was quenchedwith 2N HCl (100 mL), the organic solvent was removed by evaporation andthe residue extracted with EtOAc (3×75 mL). The combined organic layerswere dried (MgSO₄), evaporated and the residue purified bychromatography using 35% EtOAc-hexane as eluent to afford the titlecompound as a mixture of aldehydes (7.75 g; 35%). MS (CI): m/e=309 for(M+H)⁺ ;

¹ H NMR δ: 9.67 (s, 0.66H), 9.64 (s, 0.33H), 7.70-6.90 (m, 9H), 3.74 (s,1H), 3.68 (s, 2H) ppm;

EXAMPLE 117(E),(E)-5-(4-Fluorophenyl)-4-(1-methyl-1H-tetrazol-5-yl)-5-phenyl-2,4-pentadienal

A mixture of the mixed aldehydes (5.1 g; 16.56 mmole) (prepared inExample 116) and formylmethylenetriphenylphosphorane (5.05 g; 16.56mmole) and benzene (200 mL) was heated together under reflux in anitrogen atmosphere for 2 hours. The solvent was removed by evaporationand the residue purified by chromatography using 30% EtOAc-hexane aseluent to afford the product as an orange foam (4.56 g). Fractionalcrystallization from EtOAc-hexane afforded the title compound as orangecrystals (0.93 g; 17%); m.p.=137°-138° C. (crystallized fromEtOAc-hexane). MS (CI): m/e=335 for (M+H)⁺ ;

¹ H NMR δ: 9.54 (d, J=7.5 Hz, 1H), 7.47 (d, J=15.6 Hz, 1H), 7.35-6.80(m, 9H), 5.84 (dd, J=7.4 Hz, J'=15.7 Hz, 1H), 3.50 (s, 3H) ppm;

¹³ C NMR δ: 192.54, 147.86, 132.09, 131.97, 130.64, 130.41, 128.96,116.17, 115.87, 33.62 ppm.

EXAMPLE 118 Ethyl(E),(E)-9-(4-fluorophenyl-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-9-phenyl-3-oxonona-6,8-dienoate

A suspension of sodium hydride (175 mg; 80% dispersion; 5.83 mmole) indry THF (10 mL) was cooled to 0° C. and treated with ethyl acetoacetate(725 μL; 740 mg; 5.69 mmole) and stirred at 0° C. for 10 minutes.Butyllithium (2.3 mL of 2.5M solution; 5.75 mmole) was added and themixture stirred at 0° C. for 15 minutes. A solution of aldehyde (860 mg;2.57 mmole) prepared for Example 117) in dry THF (10 mL) was added andthe mixture stirred at 0° C. for 15 minutes. The reaction was quenchedby the addition of 2N HCl (30 mL) and the organic solvent removed byevaporation. The residue was extracted with EtOAc and the combinedorganic extracts were dried (MgSO₄) and evaporated. The residue waspurified by chromatography using 40% EtOAc-hexane as eluent to affordthe title compound as a yellow gum (954 mg; 80%). MS (CI): m/e=465 for(M+H)⁺ ;

IR (film) ν_(max) : 3400 (br), 1730, 1600, 1510 cm⁻¹ ;

¹ H NMR δ : 7.20-6.60 (m, 9H), 6.54 (d, J=15.6 Hz, 1H), 5.16 (dd, 1H),4.40 (br, 1H), 4.00 (q and br, 3H), 3.31 (s, 3H), 3.25 (s, 2H), 2.52 (m,2H), 1.08 (t, 3H) ppm.

EXAMPLE 119 Ethyl(±)-(E),(E)-erythro-9-(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-9-phenylnona-6,8-dienoate

A solution of the β-ketoester (950 mg; 2.045 mmole) (prepared in Example118) in dry THF (20 mL) was treated with a solution of triethylborane(2.25 mL of 1M soln. in THF: 2.25 mmole) and stirred at 23° C. for 1hour. Methanol (400 μL) was added and the mixture cooled to -78° C. andtreated with NaBH₄ (200 mg; 5.26 mmole). After 1 hour the reaction wasquenched by the addition of 2N HCl and the organic solvent removed byevaporation. The residue was extracted with EtOAc and the combinedorganic extracts were dried (MgSO₄) and evaporated. The residue waspurified by chromatography using 60% EtOAc-hexane as eluent to affordthe title compound as a yellow gum (330 mg; 35%). MS (CI): m/e=467 for(M+H)⁺ ;

IR (KBr) ν_(max) : 3400 (br), 1725, 1600, 1500 cm⁻¹ ;

¹ H NMR δ : 7.30-6.80 (m, 9H), 6.70 (dd, J=1.0 Hz, J'=15.6 Hz, 1H), 5.35(dd, J=5.9 Hz, J'=15.7 Hz, 1H), 4.41 (m, 1H), 4.25 (br s, 1H), 4.15 (q,J=7.1 Hz, 2H), 3.83 (br m, 2H), 3.52 (s, 3H), 2.45 (d, J=6.1 Hz, 2H),1.60 (m, 2H), 1.26 (t, J=6.1 Hz, 3H) ppm;

¹³ C NMR δ : 172.40, 164.47, 161.17, 153.66, 148.07, 139.94, 138.21,137.75, 135.55, 132.40, 132.30, 130.36, 129.82, 129.46, 128.67, 128.47,127.29, 121.05, 115.74, 115.45, 71.89, 69.35, 68.34, 60.83, 60.34,42.34, 41.53, 41.22, 33.56, 14.13 ppm.

EXAMPLE 120 Sodium(±)-(E),(E)-erythro-9-(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-9-phenylnona-6,8-dienoatehydrate

A solution of dihydroxyester (160 mg; 0.343 mmole) (prepared in Example119) in EtOH (5 mL) was treated with 1N NaOH (343 μL; 0.343 mmole) andthe resulting solution stirred at 23° C. for 1 hour. The solvent wasremoved by evaporation and the residue was dissolved in water (2 mL) andlyophilized to afford the title compound as a light brown solid (155mg); m.p.=130°-137° C.

IR (KBr) ν_(max) : 3400 (br), 1560, 1510 cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.50-6.80 (m, 9H), 6.51 (d, J=15.7 Hz, 1H), 5.15(dd, J=5.4 Hz, J'=15.7 Hz, 1H), 4.15 (m, 1H), 3.70 (s, 3H), 3.65 (br,1H), 3.35 (br, 2H), 1.95 (m, 2H), 1.40 (m, 2H) ppm;

¹³ C NMR (DMSO-d₆) δ : 176.42, 163.42, 153.17, 146.07, 140.03, 139.73,135.70, 135.64, 132.20, 132.09, 128.72, 128.42, 128.07, 127.98, 124.83,121.51, 115.51, 115.22, 66.22, 65.69, 44.46, 43.59, 33.42 ppm.

Anal. Calcd. for C₂₃ H₂₂ FN₄ O₄ Na.H₂ O: C, 57.74; H, 5.06; N, 11.72,Found: C, 58.70; H, 5.10; N, 11.16.

EXAMPLE 121 2(1-Methyltetrazol-5-yl)-1,1-diphenylethanol

A solution of 1,5-dimethyltetrazole (20 g; 0.204 mole) in dry THF (200mL) was cooled to -78° C. and treated with n-butyllithium (91 mL of 2.5molar solution in hexane; 0.227 mole) and the mixture stirred at -78° C.for 30 minutes. Benzophenone (31.1 g; 0.171 mole) was added and themixture stirred at -78° C. for 30 minutes and allowed to warm up to 23°C. and stirred for 15 hours. The mixture was quenched with 2N HCl (100mL) and extracted with EtOAc (3×150 mL). The combined organic layerswere dried (MgSO₄) and evaporated. The residue was crystallized fromEtOAc-Hexane to afford the title compound as a white solid (10.5 g;22%); m.p.=175°-176° C. (crystallized from EtOAc-hexane). MS (CI):m/e=281 for (M+H)⁺ ;

IR (KBr) ν_(max) : 3300 (br), 1530, 1500 cm⁻¹ ;

¹ H NMR δ : 7.50-7.20 (m, 10H), 5.45 (s, 1H), 3.82 (s, 2H), 3.80 (s, 3H)ppm;

¹³ C NMR δ : 152.36, 145.63, 128.16, 127.28, 126.05, 125.94, 77.70,35.90, 33.76 ppm;

Anal. Calcd. for C₁₆ H₁₆ N₄ : C, 68.56; H, 5.76; N, 20.00, Found: C,68.62; H, 5.81; N, 20.10.

EXAMPLE 122 2,2-Diphenyl-1-(1-methyl-1H-tetrazol-5-yl)ethene

A mixture of 2(1-methyltetrazol-5-yl)-1,1-diphenylethanol (2.15 g; 7.68mmole) and KHSO₄ (300 mg) was heated at 200° C. for 20 minutes. Thecooled mixture (50° C.) was triturated with CHCl₃ (50 mL) and theorganic solvent was decanted from the inorganic residue. Evaporationafforded the title compound as a cream solid (1.7 g; 85%);m.p.=147°-148° C. (crystallized from EtOAc-hexane). MS (CI): m/e=263 for(M+H)⁺ ;

IR (KBr) ν_(max) : 1640, 1500, 1445 cm⁻¹ ;

¹ H NMR δ : 7.50-7.00 (m, 10H), 6.78 (s, 1H), 3.43 (s, 3H) ppm;

¹³ C NMR δ : 153.94, 152.18, 140.40, 137.83, 129.54, 129.37, 128.94,128.59, 128.38, 128.28, 108.22, 33.56 ppm.

Anal. Calcd. for C₁₆ H₁₄ N₄ : C, 73.27; H, 5.38; N, 21.36 Found: C,73.25; H, 5.43; N, 21.43.

EXAMPLE 123 3,3-Diphenyl-2-(1-methyl-1H-tetrazol-5-yl)propenal

A solution of 2,2-diphenyl-1-(1-methyl-1H-tetrazol-5-yl)-ethene (3.75 g;14.29 mmole) in dry THF (40 mL) was cooled to -78° C. and treated withn-butyllithium (6.3 mL of a 2.5 M soln. in hexane; 15.75 mmole) and theresulting mixture stirred at -78° C. for 30 minutes. Ethyl formate (1.5mL; 18.58 mmole) was added and the mixture stirred at -78° C. for 2hours. The reaction was quenched with 2N HCl and the solvent removed byevaporation. The residue was extracted with EtOAc (3×30 mL) and thecombined organic layers were dried (MgSO₄) and evaporated. The residuewas purified by chromatography using 25-35% EtOAc-hexane as eluent toafford starting material (1.35 g; 36%) and the desired title compound(1.65 g; 39%); m.p.=185°-186° C. (crystallized EtOAc-hexane). MS (EI):m/e=290 for M⁺ ;

IR (KBr) ν_(max) : 1675, 1600, 1445 cm⁻¹ ;

¹ H NMR δ : 9.66 (s, 1H), 7.70-6.90 (m, 10H), 3.66 (s, 3H) ppm;

¹³ C NMR δ : 189.45, 167.79, 151.44, 138.35, 136.65, 131.54, 131.34,130.96, 129.63, 128.71, 123.55, 33.91 ppm.

Anal. Calcd. for C₁₇ H₁₄ N₄ O: C, 70.34; H, 4.87; N, 19.30,Found: C,70.63; H, 4.99; N, 19.33.

EXAMPLE 124(E)-4-(1-Methyl-1H-tetrazol-5-yl)-5,5-bis(phenyl)-2,4-pentadienal

A solution of the aldehyde (1.33 g; 4.57 mmole) (prepared in Example123) and triphenylphosphoranylidene acetaldehyde (1.5 g; 4.87 mmole) washeated under reflux in benzene (50 mL) for 24 hours. The solvent wasevaporated and the residue was purified by chromatography using 30%EtOAc-hexane as eluent to afford the title compound as a yellow foam (1g; 71%). MS (CI): m/e=317 (M+H)^(+;)

¹ H NMR δ : 9.53 (d, J=7.5 Hz, 1H), 7.55-7.10 (m, 10H), 6.69 (d, J=16Hz, 1H), 5.84 (dd, J=16 Hz, J'=7.5 Hz, 1H), 3.50 (s, 3H) ppm.

EXAMPLE 125 Methyl(E)-9,9-diphenyl-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-nona-6,8-dienoate

Methylacetoacetate (0.525 mL; 4.87 mmole) was added to a suspension ofsodium hydride (0.160 g; 80% disp. in mineral oil) in THF at 0° C. andstirred for 10 minutes. N-Butyllithium (2.14 mL; 2.5M solution inhexanes) was added and reaction stirred for 15 minutes. This solutionwas added to a solution of the aldehyde (1.0 g; 3.2 mmole) (prepared inExample 124) in THF at 0° C. and stirred for 30 minutes. The reactionwas treated with 2N HCl (30 mL) and extracted with EtOAc (3×15 mL). Theorganic layer was dried with MgSO₄ and evaporated. The crude residue wastriturated with hexane (3×25 mL) then dissolved in THF/CH₃ OH (4:1; 20mL) and treated with triethylborane (3.2 mL; 1M solution in THF). Airwas bubbled through the solution for 10 minutes and the reaction stirredfor an additional 50 minutes. The solution was then cooled to -78° C.and treated with sodium borohydride (120 mg; 3.2 mmole) and stirred for1 hour. The reaction was quenched with 2M HCl (100 mL) and extractedwith EtOAc (3×20 mL). The organic layers were dried with MgSO₄ andevaporated. The residue was dissolved in CH₃ OH (30 mL) and stirred for15 hours. The solvent was evaporated and residue purified bychromatography using 50% EtOAc-hexane as eluent to afford the titlecompound as a yellow oil (470 mg; 33%). MS (CI): m/e=435 (M+H)⁺ ;

¹ H NMR δ : 7.80-6.80 (m, 10H), 6.71 (d, J=16 Hz, 1H), 5.34 (dd, J=16Hz, J'=6 Hz, 1H), 4.60-4.10 (m, 2H), 3.70 (s, 3H), 3.52 (s, 3H), 2.45(d, J=6 Hz, 2H), 1.70-1.50 (m, 2H) ppm.

EXAMPLE 126 Sodium(±)-(E)-erythro-9,9-diphenyl-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-nona-6,8-dienoatehydrate

The methyl ester (470 mg; 1.08 mmole) (prepared in Example 125) wasdissolved in ethanol (10 mL) and treated with 1N NaOH (1.08 mL). Thereaction was stirred for 1 hour. The solvent was evaporated and residuewas freeze-dried to afford a light yellow powder (500 mg; 100%);m.p.=145°-150° C.

IR ν_(max) : 3400 (br), 1610, 1425, 1360 cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.60-6.60 (m, 10H), 6.52 (d, J=16 Hz, 1H), 5.12(dd, J=16 Hz, J'=5.5 Hz, 1H), 4.20-4.05 (m, 1H), 3.80-3.55 (m, 1H), 3.70(s, 3H), 3.10 (br s, 2H) 2.10-1.10 (m, 5H) ppm.

Anal. Calcd. for C₂₃ H₂₃ N₄ O₄ Na.H₂ O: C, 59.99; H, 5.47; N, 12.17Found: C, 59.18; H, 5.46; N, 10.96.

EXAMPLE 127 2,2-Bis(4-methoxyphenyl)-1-(1-methyl-1H-tetrazol-5-yl)ethene

A solution of 1,5-dimethyltetrazole (20 g; 0.204 mole) in dry THF (200mL) was cooled to -78° C. and treated with n-butyllithium (91 mL of 2.5Msolution in hexane; 0.227 mole) and the mixture stirred at -78° C. for30 minutes. 4,4'-Dimethoxybenzophenone (41.3 g; 0.171 mole) was addedand the mixture stirred at -78° C. for 30 minutes, and allowed to warmup to 23° C. over 2 hours. The mixture was acidified with 2N HCl (100mL) and the organic solvent removed by evaporation. The residue wasextracted with EtOAc (3×300 mL) and the combined organic layers weredried (MgSO₄) and evaporated. The residue was crystallized fromEtOAc-hexane to afford a light brown solid (48 g) which was found to bea mixture of the desired product and the initial aldol adduct(1,1-bis(4-methoxyphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol). Thismixture was dissolved in xylene (180 mL) and heated under reflux for 1hour with p-toluenesulfonic acid in a Dean-Stark apparatus. The cooledmixture was diluted with ether (100 mL) and the resulting solid removedby filtration to afford the title compound as a cream solid (40 g);m.p.=146°-147° C. (crystallized from EtOAc-hexane). MS (CI): m/e=323 for(M+H)⁺ ;

IR (KBr) ν_(max) : 1605, 1520, 1250 cm⁻¹ ;

¹ H NMR δ : 7.31 (d, J=7.8 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.90 (d,J=7.8 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.62 (s, 1H), 3.84 (s, 3H), 3.79(s, 3H), 3.42 (s, 3H) ppm;

¹³ C NMR δ : 160.79, 160.16, 153.29, 133.33, 131.25, 130.32, 129.95,127.36, 114.14, 113.69, 105.57, 55.40, 55.28, 33.71 ppm.

Anal. Calcd. for C₁₈ H₁₈ N₄ O₂ : C, 67.07; H, 5.63; N, 17.38 Found: C,66.93; H, 5.63; N, 17.05.

EXAMPLE 1283,3-Bis(4-methoxyphenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal

A solution of the olefin (4.6 g; 14.29 mmole) (prepared in Example 127)in dry THF (50 mL) was cooled to -78° C. and treated with n-butyllithium(6.3 mL of a 2.5M solution in hexane; 15.75 mmole) and the resultingsolution stirred at -78° C. for 30 minutes. Ethyl formate (1.5 mL) wasadded and the mixture stirred at -78° C. for 2 hours. The mixture wasquenched with 2N HCl and the organic solvent removed by evaporation. Theresidue was extracted with EtOAc (3×33 mL) and the combined organiclayers were dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using 25-35% EtOAc-hexane as eluent to affordstarting material (0.84 g; 18%). Further elution afforded the desiredtitle compound (1.78 g; 36%); m.p.=130°-131° C. (crystallized fromEtOAc-hexane). MS (CI): m/e 351 for (M+H)⁺ ;

IR (KBr) ν_(max) : 1675, 1605, 1515, 1260 cm⁻¹ ;

¹ H NMR δ : 9.59 (s, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.7 Hz,1H), 6.90 (d, J=8.9 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 3.90 (s, 3H), 3.77(s, 3H), 3.67 (s, 3H) ppm;

¹³ C NMR δ : 189.51, 167.47, 162.59, 161.98, 152.30, 133.91, 132.29,130.79, 129.35, 121.05, 114.20, 114.15, 55.80, 55.40, 33.94 ppm.

Anal. Calcd. for C₁₉ H₁₉ N₄ O₃ : C, 65.14; H, 5.18; N, 15.99 Found: C,64.96; H, 5.22; N, 15.75.

EXAMPLE 1295,5-Bis-(4-methoxyphenyl)-4-(1-methyl-1H-tetrazol-5yl)-penta-2,4-dienal

A solution of3,3-bis(4-methoxyphenyl)-2-(1-methyl-1H-tetrazol-5-yl)propenal (1.7 g;4.86 mmole) in benzene (100 mL) was treated withtriphenylphosphoranylidene acetaldehyde (1.55 g; 5.1 mmole) and heatedunder reflux for 3 hours. The solvent was removed by evaporation and theresidue purified by chromatography using 30% EtOAc-hexane as eluent toafford the title compound as a yellow foam (1.35 g; 74%). MS (CI):m/e=377 for (M+H)⁺ ;

IR (KBr) ν_(max) : 1675, 1590, 1510 cm⁻¹ ;

¹ H NMR δ : 9.52 (d, J=7.6 Hz, 1H), 7.53 (d, J=14.2 Hz, 1H), 7.23 (d,J=8.5 Hz, 1H), 7.00 (d, J=9.3 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 6.70 (d,J=8.9 Hz, 1H), 5.83 (dd, J=7.6 Hz, J'=15.7 Hz, 1H), 3.91 (s, 3H), 3.75(s, 3H), 3.50 (s, 3H) ppm;

¹³ C NMR δ : 192.89, 161.40, 160.97, 157.91, 153.29, 149.41, 133.90,132.77, 132.29, 132.00, 131.71, 131.65, 131.25, 130.81, 117.21, 114.18,114.12, 55.49, 55.32, 33.61 ppm.

EXAMPLE 130 Ethyl(E)-9,9-bis(4-methoxyphenyl)-5-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-3-oxonona-6,8-dienoate

Ethyl acetoacetate (825 μL; 842 mg; 6.48 mmole) was added to asuspension of NaH (206 mg; 80% dispersion; 6.86 mmole) in dry THF (20mL) at 0° C. and the resulting mixture stirred at 0° C. for 10 minutes.A solution of n-butyllithium (2.7 mL of 2.5M solution in hexane; 6.75mmole) was added and the mixture stirred at 0° C. for 10 minutes. Asolution of the aldehyde (1.3 g; 3.46 mmole) (prepared in Example 129)in dry THF (20 mL) was added and the mixture stirred at 0° C. for 15minutes. After 2N HCl was added to quench the reaction, the solvent wasremoved by evaporation. The residue was diluted with water (30 mL),extracted with EtOAc (2×20 mL) and the combined organic layers weredried (MgSO₄) and evaporated. The residue was purified by chromatographyusing 40% EtOAc-hexane as eluent to afford the title compound as ayellow foam (1.165 g; 66%).

IR (KBr) ν_(max) : 3450 (br), 1750, 1710, 1610, 1510 cm⁻¹ ;

¹ H NMR δ : 7.30-6.60 (m, 9H), 5.27 (dd, J=6.1 Hz, J'=15.9 Hz, 1H), 4.68(brs, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 3.69 (s, 3H), 3.47 (s,3H) 3.43 (s, 2H), 3.17 (brs, 1H), 2.70 (d, J=6.0 Hz, 2H), 1.23 (t, J=6.0Hz, 3H) ppm;

¹³ C NMR δ : 202.48, 160.09, 159.70, 154.16, 149.40, 134.16, 132.57,132.14, 131.99, 131.22, 129.08, 118.34, 113.79, 68.17, 61.47, 55.34,55.17, 49.94, 49.33, 33.56, 14.09 ppm.

EXAMPLE 131 Ethyl(±)-(E)-erythro-9,9-bis(4-methoxyphenyl)-3,5-dihydroxy-8(1-methyl-1H-tetrazol-5-yl)nona-6,8-dienoate

A solution of the β-ketoester (1 g; 1.97 mmole) (prepared in Example130) in dry THF (50 mL) and methanol (300 μL) was treated with asolution of triethylborane (2.15 mL of 1M in THF) and the mixturestirred at 23° C. for 1 hour. The solution was cooled to -78° C. andtreated with NaBH₄ (110 mg; 2.92 mmole). After 1 hour at -78° C. thereaction was quenched with 2N HCl and the solvent was removed byevaporation. The residue was diluted with water and extracted with EtOAc(3×30 mL). The combined organic extracts were dried (MgSO₄) andevaporated. The residue was purified by chromatography to afford thetitle compound as a light oil (136 mg).

IR (KBr) ν_(max) : 3450 (br), 1750, 1710, 1610, 1510 cm⁻¹.

¹ H NMR δ : 7.70-6.50 (m, 9H), 5.80 (dd, 1H), 4.45 (br, 1H), 4.15 (q,2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.50 (s, 3H), 2.45 (m, 2H), 1.55 (m,2H), 1.26 (t, 3H) ppm;

¹³ C NMR δ : 172.38, 160.18, 159.29, 154.32, 148.92, 138.54, 136.19,132.81, 132.29, 132.20, 132.11, 131.90, 131.51, 131.22, 128.59, 128.41,128.36, 118.97, 113.90, 113.34, 72.15, 66.31, 60.75, 55.35, 55.20,42.74, 42.14, 41.73, 41.48, 33.50, 14.18.

EXAMPLE 132 Sodium(±)-(E)-erythro-9,9-bis(4-methoxyphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)nona-6,8-dienoatedihydrate

A solution of the ester (95 mg; 0.196 mmole) (prepared in Example 131)in ethanol (15 mL) was treated with 1N NaOH solution (196 μL) and themixture stirred at 23° C. for 1 hour. The solvent was removed byevaporation and the residue was dissolved in water (2 mL) and freezedried to afford the title compound as a brown powder (95 mg; 100%);m.p.=175°-180° C.

IR (KBr) ν_(max) : 3400 (br), 1600, 1575, 1510 cm⁻¹ ;

¹ H NMR (DMSO-d₆) δ : 7.70-6.65 (m, 9H), 6.55 (d, J=15.5 Hz, 1H), 5.08(dd, J=5.6 Hz, J'=15.7 Hz, 1H), 4.14 (br, 1H), 3.75 (s, 3H), 3.67 (s,3H), 3.66 (s, 3H), 2.10-1.80 (br, 2H), 1.50-1.20 (br, 2H) ppm;

¹³ C NMR (DMSO-d₆ δ : 159.25, 158.80, 153.78, 138.13, 132.75, 131.88,131.60, 131.42, 131.30, 130.41, 128.68, 128.53, 125.72, 113.74, 113.48,68.56, 65.89, 55.14, 54.99, 44.68, 43.68, 33.34.

Anal. Calcd. for C₂₅ H₂₇ NaN₄ O₆.2H₂ O: C, 55.76; H, 5.81; N, 10.41Found: C, 54.43; H, 5.04; N, 8.15.

EXAMPLE 133 Cis-2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-aceticacid methyl ester

Methyl 3,5-dihydroxy-7-phenyl-6-enoate (98% diastereomeric purity) (2.37g, 9.48 mmol) was stirred with 2,2-dimethoxypropane (20 mL) and acatalytic amount of p-toluenesulfonic acid for 16 hours. The solutionwas partitioned between diethyl ether and dilute aqueous sodiumbicarbonate solution. The organic layer was dried (Na₂ SO₄) andconcentrated under reduced pressure to afford a yellow solid. Afterrecrystallization from isopropyl ether, 1.70 g (62%) of the titlecompound was obtained as a white solid; m.p.=84°-86.5° C.

Alternatively, 0.2 g of solid sodium carbonate can be added to the2,2-dimethoxypropane solution and the solution stirred vigorously. Thesolid is filtered through a fluted filter paper. The excess2,2-dimethoxypropane is removed under reduced pressure to afford ayellow solid which is recrystallized from isopropyl ether.

¹ H NMR (CDCl₃) δ : 7.37-7.19 (5H, m), 6.59 (1H, d, J=15.9 Hz), 6.14(1H, dd, J=15.9, 6.4 Hz), 4.57-4.35 (1H, m), 4.42-4.35 (1H, m), 3.68(3H, s), 2.58 (1H, d, J=15.6, 6.9 Hz), 2.14 (1H, dd, J=15.6, 6.3 Hz),1.74-1.61 (1H, m), 1.52 (3H, s), 1.43 (3H, s), 1.45-1.35 (1H, m).

Anal. Calcd. for C₁₇ H₂₂ O₄ : C, 70.32; H, 7.63 Found: C, 70.24; H,7.69.

EXAMPLE 134 Cis-2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-aceticacid

A solution of 2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acidmethyl ester (8.5 g, 29.3, mmol) in 1N NaOH (32 mL) and methanol (64 mL)was heated to reflux for 45 minutes. After evaporation under reducedpressure, the aqueous solution was washed once with diethyl ether andacidified with 1N HCl (33 mL). The precipitate was collected andrecrystallized from ethyl acetate/isopropyl ether to afford 7.2 g (90%)of the title compound as a colorless solid; m.p.=153°-155° C.

¹ H NMR (CDCl₃) δ : 7.37-7.20 (5H, m), 6.60 (1H, d, J=16.0 Hz), 6.14(1H, dd, J=16.0, 6.4 Hz), 4.59-4.54 (1H, m), 4.43-4.35 (1H, m), 2.62(1H, dd, J=16.0, 7.2 Hz), 2.51 (1H, dd, J=16.0, 5.3 Hz), 1.77-1.72 (1H,m), 1.54 (3H, s), 1.46 (3H, s), 1.50-1.36 (1H, m).

Anal. Calcd. for C₁₆ H₂₀ O₄ : C, 69.54; H, 7.30 Found: C, 69.20; H,7.33.

EXAMPLE 135 Resolution ofcis-2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acid

The racemic cis-2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-aceticacid (0.31 g, 1.1 mmol) (prepared in Example 134) was dissolved in aboiling solution of hexane/ethanol containing (1S,2R)-ephedrine (0.2 g,1.1 mmol). The resulting solution was very slowly brought to roomtemperature to give 0.21 g (41.4%) of colorless chiral salt (the usageof diastereomerically pure seed crystal is recommended during theresolution): m.p.=170°-171° C.

The chiral acid was freed through an acidic workup (vide infra) and itsenantiomeric purity was determined to be 100% by ¹ H NMR usingL-phenyltrifluoromethyl carbinol as a chiral solvent. [α]_(D) ²⁵-+5.45°(c=1, CHCl₃).

EXAMPLE 136 Cis-(4R,6S)-2,2-dimethyl-6-formyl-1,3-dioxane-4-acetic acid

The resolved salt ofcis-2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acid and(1S,2R)-ephedrine (6.6 g, 14.9 mmol) (prepared in Example 135) waspartitioned between 0.5N HCl (30 mL) and diethyl ether. The ether layerwas washed with brine, dried (MgSO₄ /Na₂ SO₄), and concentrated underreduced pressure to afford 4.1 g (99.6%) of the free acid. This acid wasdissolved in dry methylene chloride (100 mL) and ozone was passedthrough this solution at -78° C. until there was deep blue coloration.Excess ozone was removed by purging with nitrogen and the ozonide formedwas decomposed by adding CH₃ SCH₃ (5 mL) and warming the solution toroom temperature and allowed to stand for 16 hours. The solution wasconcentrated under reduced pressure and the residue was dissolved inisoamyl ether (ca 100 mL). The benzaldehyde which was formed during theozonolysis was azeotroped together with isoamyl ether under reducedpressure to afford the title compound.

¹ H NMR (CDCl₃) δ : 9.57 (1H, s), 4.40-4.30 (2H, m), 2.60 (1H, dd,J=16.0, 7.0 Hz), 2.49 (1H, dd, J=16.0, 6.0 Hz), 1.88-1.83 (1H, m) 1.49(3H, s), 1.46 (3H, s), 1.42-1.31 (1H, m).

EXAMPLE 137Cis-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-2,2-dimethyl-1,3-dioxane-4-aceticacid

The crude chiral acid prepared in Example 136 was dissolved in dry THF(50 mL) and the resulting solution was transferred to a 250 mLthree-neck flask purged with nitrogen and equipped with a mechanicalstirrer. After the solution was stirred vigorously and cooled to -78°C., n-BuLi (2.5M in hexane, 5.96 mL) was added dropwise. Toward the endof addition, the solution turned into a suspension of white solid-likegel.

A separate flask containing dimethyl[3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5yl)-2-propen-1-yl]phosphonate(6.2 g, 14.7 mmol) (prepared in Example 112) in THF (50 mL) under anitrogen atmosphere was cooled to -78° C. and n-BuLi (2.5M in hexane,5.96 mL) was added slowly. The resulting red-brown solution was stirredfor 15 minutes at -78° C. This solution of phosphonate anion wastransferred through a double ended needle to the above vigorouslystirred suspension at -78° C. containing the lithium salt of the chiralacid. After the addition, the resulting brown solution was stirred for30 minutes at -78° C. and 16 hours at ambient temperature. The THFsolution was partitioned between 0.5N HCl and ethyl acetate. The organicphase was washed with brine (2x), dried (Na₂ SO₄), and concentratedunder reduced pressure. The residue was chromotagraphed on silica gel(66:33:1/diethyl ether:hexane:acetic acid) to afford 3.80 g (51.6%overall yield from the initial ephedrine salt; toluene was employed toazeotrope the residual acetic acid) of the title compound as a yellowform. [α]_(D) ²⁵ =+106.1° (c=2.23, CHCl₃).

¹ H NMR (CDCl₃) δ : 7.24-6.82 (8H, m), 6.62 (1H, d, J=15.0 Hz), 5.32(1H, dd, J=15.0, 5.7 Hz), 4.42-4.37 (1H, m), 4.30-4.23 (1H, m), 3.51(3H, s), 2.53 (1H, dd, J=15.9, 7.0 Hz), 2.42 (1H, dd, J=15.9, 5.6 Hz),1.62-1.57 (1H, m), 1.46 (3H, s), 1.33 (3H, s), 1.30-1.20 (1H, m).

EXAMPLE 138Trans-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one

Cis-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-2,2-dimethyl-1,3-dioxane-4-aceticacid (3.7 g, 7.45 mmol) was dissolved in a solution of THF (90 mL) and0.2N HCl (60 mL) and allowed to stand for 16 hours. The solution waspartitioned between ethyl acetate and water. The organic layer waswashed with brine (2x), dried (Na₂ SO₄), and concentrated under reducedpressure. The residue was dissolved in dry methylene chloride (60 mL)and stirred for 4 hours in the presence of1-cyclohexyl-3-(2-morpholinomethyl) carbodiimidemetho-p-toluenesulfonate (6.6 g, 15.6 mmol). The solution wasconcentrated under reduced pressure and the residue was partitionedbetween ethyl acetate and water. The organic layer was dried (Na₂ SO₄)and concentrated under reduced pressure. The residue was purified bychromatography on silica gel (1:1/ethyl acetate:diethyl ether). Afterrecrystallization from ethyl acetate-hexane, 1.33 g (40.1%) of the titlecompound was obtained as a white solid; m.p.=172°-173° C. [α]_(D) ²⁵=+237.8° (c=2.17, CHCl₃).

EXAMPLE 139 Methyl 3-hydroxy-5-oxo-6,8-decadienoate

To a cold (-30° C.) solution of methyl acetoacetate (41.5 g, 357 mmol)in THF (500 mL) was added lithium diisopropylamide (476 mL, 1.5Msolution in cyclohexane, 714 mmol). The resultant solution was stirredfor 15 minutes at -30° C. After cooling to -78° C., 2,4-hexadienal (34.3g, 357 mmol) was added and the solution stirred for 10 minutes at -78°C. and for 16 hours at ambient temperature. The solution wasconcentrated under reduced pressure and the residual syrup waspartitioned between 1N HCl and ethyl acetate. The organic layer waswashed with brine (2x), dried (Na₂ SO₄), and concentrated. The residuewas purified by chromatography on silica gel (diethyl ether:hexane/2:1)to afford 18.5 g (24.4%) of the title compound as an oil.

¹ H NMR for (E) (E) isomer (200 MHz, CDCl₃) δ : 6.3 (1H, dd, J=14.7,11.9 Hz), 6.02 (1H, dd, J=14.7, 11.9 Hz), 5.75 (1H, dq, J=14.7, 6.4 Hz),5.5 (1H, dd, J=18.7, 6.4 Hz), 4.74-4.5 (1H, m), 3.73 (3H, s), 3.51 (2H,s), 2.6 (2H, d, J=5.8 Hz), 1.77 (3H, d, J=6.4 Hz).

EXAMPLE 140 Methyl 3,5-dihydroxy-6,8-decadienoate

To a cold (-15°C.) solution of methyl 3-hydroxy-5-oxo-6,8-decadienoate(18.5 g, 86.9 mmol) in THF (300 mL) was added triethylborane (1M in THF,113 mL, 113 mmol) and the solution was stirred for 20 minutes. After themixture was cooled to -78° C., NaBH₄ (6 g, 159 mmol) and methanol (37.5mL) were added. The solution was vigorously stirred for 30 minutes at-78° C. and at ambient temperature for 3 hours. The solvent was removedunder reduced pressure and the residue was partitioned between 1N HCland ethyl acetate. The organic layer was dried (Na₂ SO₄) andconcentrated. The residue was purified by chromatography on silica gel(diethyl ether:hexane/3:1) to afford 7.95 g (42.7%) of the titlecompound as a yellow oil.

¹ H NMR for (E) (E) isomer (360 MHz, CDCl₃) δ : 6.18 (1H, dd, J=15.1,10.4 Hz), 6.00 (1H, dd, J=15.1, 10.4 Hz), 5.69 (1H, dq, J=15.1, 7.0 Hz),5.52 (1H, dd, J=15.1, 6.7 Hz), 4.46-4.37 (1H, m), 4.29-4.22 (1H, m),3.69 (3H, s), 2.60-2.42 (2H, m), 1.72 (3H, d, J=7.0 Hz), 1.74-1.57 (2H,m).

EXAMPLE 141 Methylcis-4-(1,3-pentadienyl)-1,5-dioxaspiro[5.5]undecane-2-acetate

Methyl 3,5-dihydroxy-6,8-decadienoate (7.6 g, 35.5 mmol) andp-toluenesulfonic acid (0.1 g) was added to cyclohexanone (10 g, 100mmol) and stirred for 16 hours at ambient temperature. The yellowsolution was loaded directly onto a silica gel column and the producteluted with diethyl ether:hexane (1:4). The appropriate fractions werecombined to give 3.52 g (33.6%) of the title compound as a colorlessoil.

¹ H NMR for (E) (E) isomer (360 MHz, CDCl₃) δ : 6.16 (1H, dd, J=15.1,10.6 Hz), 6.00 (1H, dd, J=15.1, 10.6 Hz), 5.71-5.65 (1H, dd, J=15.1, 6.5Hz), 5.47 (1H, dd, J=15.1, 6.4 Hz), 4.44-4.39 (1H, m), 4.35-4.30 (1H,m), 3.66 (3H, s), 2.52 (1H, dd, J=1.54, 7.9 Hz), 2.30 (1H, dd, J=15.4,6.5 Hz), 2.1-1.18 (12H, m), 1.72 (3H, d, J=6.5 Hz).

Anal. Calcd. for C₁₇ H₂₆ O₄ : C, 69.36; H, 8.90, Found: C, 69.59; H,9.16.

EXAMPLE 142 Cis-4-(1,3-pentadienyl)-1,5-dioxaspiro[5.5]undecane-2-aceticacid

Methyl 4-(1,3-pentadienyl)-1,5-dioxaspiro[5.5]undecane-2-acetate (3.5 g,12.4 mmol) was heated to reflux in a solution of 1N NaOH (13 mL) andmethanol (26 mL). Methanol was removed under reduced pressure and theremaining aqueous solution was acidified with 1N HCl and extracted withdiethyl ether. The organic layer was dried (Na₂ SO₄) and concentrated.The residual solid was recrystallized from ethyl acetate/hexane toafford 2.0 g (55.9%) of the title compound as a colorless solid;m.p.=144°-146.5° C.

¹ NMR (360 MHz, CDCl₃) δ : 6.18 (1H, dd, J=18.0, 12.5 Hz), 5.72 (1H, dq,J=18.0, 7.7 Hz), 5.99 (1H, dd, J=18.0, 12.5 Hz), 5.48 (1H, dd, J=18.0,7.6 Hz), 4.45-4.37 (1H, m), 4.37-4.25 (1H, m), 2.56 (1H, dd, J=18.9, 8.8Hz), 2.48 (1H, dd, J=18.9, 6.1 Hz), 2.60-1.30 (12H, m), 1.73 (3H, d,J=7.7 Hz).

Anal. Calcd. for C₁₆ H₂₄ O₄ : C, 68.54; H, 8.62 , Found: C, 68.36; H,8.55.

EXAMPLE 143Cis-4-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-1,5-dioxaspiro[5.5]undecane-2-aceticacid A. 4-Formyl-1,5-dioxaspiro[5.5]undecane-2-acetic acid

Ozone was passed through a solution of4-1,3-pentadienyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid (570 mg,2.0 mmol) in methylene chloride (25 mL) at -78° C. After the solutionhad attained a blue color, nitrogen was passed through the solution toremove the excess ozone. Dimethyl sulfide (0.5 mL) was added and thesolution was concentrated under reduced pressure to afford the titlecompound as a viscous oil which was used without further purification inthe subsequent step.

¹ H NMR (60 MHz, CDCl₃) δ : 9.57 (1H, s), 4.52-4.14 (2H, m), 2.60-2.31(2H, m), 2.10-1.10 (12H, m).

B.Cis-4-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-1,5-dioxaspiro[5.5]-undecane-2-acid

To a solution of dimethyl[3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenyl]phosphonate(1.7 g, 4 mmol) in THF (20 mL) at -78° C. was added n-BuLi (1.6 mL, 4mmol, 2.5M in hexane). The resultant brown-red solution was stirred for30 minutes at -78° C. Using a double ended needle, this solution wastransferred to a solution containing4-formyl-1,5-dioxaspiro[5.5]undecane-2-acetic acid (prepared in Step A)in THF (10 mL) and maintained at -78° C. After the transfer had beencompleted, the combined reaction mixture was stirred at -78° C. for 1hour and at ambient temperature for 4 hours. The solution was thenpartitioned between 0.5N HCl and ethyl acetate. The organic layer waswashed with brine (2x), dried (Na₂ SO₄), and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(diethyl ether:hexane:acetic acid/50:20:1) to afford 342 mg (31.9%overall yield) of the title compound as a yellow foam.

¹ H NMR (360 MHz, CDCl₃) δ : 7.25-6.84 (8H, m), 6.66 (1H, d, J=16.0 Hz),5.32 (1H, dd, J=16.0, 5.1 Hz), 4.45-4.25 (2H, m), 3.52 (3H, s), 2.56(1H, dd, J=16.0, 7.6 Hz), 2.44 (1H, dd, J=16.0, 5.1 Hz), 1.89-1.17 (12H,m).

EXAMPLE 144Trans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one

A mixture of4-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-1,5-dioxaspiro[5.5]undecane-2-aceticacid (280 mg, 0.52 mmol) in 20 mL of THF/0.5N HCl (1:1) was allowed tostand at ambient temperature for 26 hours. The solution was partitionedbetween brine and ethyl acetate. The organic layer was washed with brine(2x), dried (Na₂ SO₄) and concentrated. The resultant foam (126 mg) wasdissolved in dry methylene chloride (10 mL) and treated with1-cyclohexyl-3-(2-morpholinomethyl) carbodiimidemetho-p-toluenesulfonate (0.24 g). After 16 hours at ambienttemperature, the solution was evaporated under reduced pressure and theresidue was purified by silica gel chromatography using ethyl acetate aseluent. The appropriate fractions afforded 38 mg (16.6%) of the titlecompound as a colorless oil which is a racemic mixture of the compoundof Example 7.

EXAMPLE 145 Methyl 2,2-dimethyl-6-formyl-1,3-dioxane-4-acetate

Cis-2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acid methylester (prepared in Example 133) was dissolved in methanol (10 mL) andozone was passed through the solution at -78° C. until the color of thesolution turned blue. The reaction mixture was purged with nitrogen toremove excess ozone then dimethyl sulfide was added and the temperaturewas allowed to warm up to room temperature. The reaction was evaporatedin vacuo and the residual oil was purified by chromatography on silicagel using diethyl ether-hexane (3:1) as the eluent to afford the titlecompound.

¹ H NMR (360MHz, CDCl₃) δ : 9.53 (1H, s), 4.40-4.23 (2H, m), 3.69 (3H,s), 2.53 (1H, dd, J=15.8, 7.02 Hz), 2.37 (1H, dd, J=15.8, 5.98 Hz),1.85-1.76 (1H, m), 1.44 (3H, s), 1.40 (3H, s), 1.35-1.23 (1H, m).

EXAMPLE 146

The general procedures of Example 80, Steps B, C and D, and Examples112, 137 and 138 are sequentially repeated, except that the4,4'-difluorobenzophenone utilized in Example 80, Step B is replaced byan equimolar amount of

(a) 2,2',4,4'-tetramethoxybenzophenone

(b) 3,3',4,4'-tetramethoxybenzophenone

(c) 2,2',4,4'-tetramethylbenzophenone

(d) 3,3',4,4'-tetramethylbenzophenone

(e) 3,3',5,5'-tetramethylbenzophenone

(f) 4'-fluoro-2,4,6-trimethylbenzophenone

(g) 2,2',3,3',4,4'-hexamethoxybenzophenone

(h) 2,2',4,4',6,6'-hexamethylbenzophenone

(i) 4'-methoxy-2,5-dimethylbenzophenone

(j) 4'-methoxy-2,4,6-trimethylbenzophenone

(k) 2,2',4,4'-tetrachlorobenzophenone

(l) 2,2',5,5'-tetrachlorobenzophenone

(m) 2,2',6,6'-tetrachlorobenzophenone

(n) 3,3'-dichlorobenzophenone

(o) 4,4'-dichlorobenzophenone

(p) 2,2'-dichloro-4,4'-dimethoxybenzophenone

(q) 2,4-dichloro-4'-trifluoromethylbenzophenone

(r) 2,2'-difluorobenzophenone

(s) 3,3'-difluorobenzophenone

(t) 2,2'-dimethoxybenzophenone

(u) 2,2'-dimethoxy-3,3'-dimethylbenzophenone

(v) 2,2'-dimethoxy-5,5'-dimethylbenzophenone

(w) 2,4-dimethoxy-2'-trifluoromethylbenzophenone

(x) 2,4-dimethoxy-4'-trifluoromethylbenzophenone

(y) 2',4'-dimethoxy-2,4,6-trimethylbenzophenone

(z) 2,2'-dimethylbenzophenone

(aa) 3,3'-dimethylbenzophenone

(bb) 4,4'-dimethylbenzophenone

(cc) 4'-fluoro-2,4-dimethoxybenzophenone

(dd) 4,4'-bis(trifluoromethyl)benzophenone

(ee) 4'-chloro-2,4,6-trimethylbenzophenone

(ff) 4,4'-dibromobenzophenone

(gg) 2,2'-dibromo-4,4'-dimethoxybenzophenone

(hh) 2-chloro-4,4'-dimethoxybenzophenone and

(ii) 2,2'-dichlorobenzophenone, respectively

and there is thereby produced

(a)Trans-(4R,6S)-6-[4,4-bis(2,4-dimethoxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(b)Trans-(4R,6S)-6-[4,4-bis(3,4-dimethoxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.

(c)Trans-(4R,6S)-6-[4,4-bis(2,4-dimethylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(d)Trans-(4R,6S)-6-[4,4-bis(3,4-dimethylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2one,

(e) Trans-(4R,6S)-6-[4,4-bis(3,5-dimethylphenyl)-3-(1-methyl-1H,tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(f)Trans-(4R,6S)-6-[4-(4-fluorophenyl)-4-(2,4,6-trimethyl-phenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(g)Trans-(4R,6S)-6-[4,4-bis(2,3,4-trimethoxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(h)Trans-(4R,6S)-6-[4,4-bis(2,4,6-trimethylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(i)Trans-(4R,6S)-6-[4-(4-methoxyphenyl)-4-(2,5-dimethylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(j)Trans-(4R,6S)-6-[4-(4-methoxyphenyl),4-(2,4,6-trimethylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(k)Trans-(4R,6S)-6-[4,4-bis(2,4-dichlorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(k)Trans-(4R,6S)-6-[4,4-bis(2,5-dichlorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(l)Trans-(4R,6S)-6-[4,4-bis(2,6-dichlorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2one,

(m)Trans-(4R,6S)-6-[4,4-bis(3-chlorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(n)Trans-(4R,6S)-6-[4,4-bis(4-chlorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2one,

(o)Trans-(4R,6S)-6-[4,4-bis(2-chloro-4-methoxyphenyl)-3-(1-methyl-1H-tetrazol-5yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(p)Trans-(4R,6S)-6-[4-(2,4-dichlorophenyl)-4-(4-trifluoromethylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(q)Trans-(4R,6S)-6-[4,4-bis(2-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2one,

(r)Trans-(4R,6S)-6-[4,4-bis(3-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(s)Trans-(4R,6S)-6-[4,4-bis(2-methoxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(t)Trans-(4R,6S)-6-[4,4-bis(2-methoxy-3-methylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(u)Trans-(4R,6S)-6-[4,4-bis(2-methoxy-5-methylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2one,

(v)Trans-(4R,6S)-6-[4-(2,4-dimethoxy-4-(2-trifluoromethyl-phenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(w)Trans-(4R,6S)-6-[4-(2,4-dimethoxy-4-(4-trifluoromethyl-phenyl)-3-(1-methyl-1H-tetrazol-5yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(x)Trans-(4R,6S)-6-[4-(2,4-dimethoxy-4-(2,4,6-trimethylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(z)Trans-(4R,6S)-6-[4,4-bis(2-methylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(aa)Trans-(4R,6S)-6-[4,4-bis(3-methylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(bb)Trans-(4R,6S)-6-[4,4-bis(4-methylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(cc)Trans-(4R,6S)-6-[4-(4-fluorophenyl)-4-(2,4-dimethoxy-phenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(dd)Trans-(4R,6S)-6-[4,4-bis(4-trifluoromethylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(ee)Trans-(4R,6S)-6-[4-(4-chlorophenyl)-4-(2,4,6-trimethylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(ff)Trans-(4R,6S)-6-[4,4-bis(4-bromophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(gg)Trans-(4R,6S)-6-[4,4-bis(2-bromo-4-methoxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

(hh)Trans-(4R,6S)-6-[4-(2-chloro-4-methoxyphenyl)-4-(4-methoxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,and

(ii)Trans-(4R,6S)-6-[4,4-bis(2-chlorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.

EXAMPLE 147 MethylN-[9,9-bis(4-fluorophenyl)-3(R),5(S)-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-1oxo-6,8-nonadien-1-yl]-L-leucinate

When a solution oftrans-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-onein tetrahydrofuran is treated with at least one equivalent of L-leucinemethyl ester (prepared in situ from the hydrochloride salt) and heatedto reflux temperature, the title compound is thereby produced.

EXAMPLE 148

The general procedure of Example 147 or Example 1 in U.S. Pat. No.4,678,806 is repeated, except that the L-leucine methyl ester utilizedtherein is replaced by an equimolar amount of

(a) L-serine methyl ester,

(b) L-phenylalanine methyl ester and

(c) L-tyrosine methyl ester, respectively there is thereby produced

(a) methylN-9,9-bis(4-fluorophenyl)-3(R),5(S)-dihydroxy-8-(1-methyl-1H-tetrazol-5yl)-1-oxo-6,8-nonadien-1-yl]-L-serinate,

(b) methylN-9,9-bis(4-fluorophenyl)-3(R),5(S)-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-1-oxo-6,8-nonadien-1-yl]-L-phenylalaninateand

(c) methylN-9,9-bis(4-fluorophenyl)-3(R),5(S)-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-1-oxo-6,8-nonadien-1-yl]-L-tyrosinate.

EXAMPLE 149N-[9,9-bis(4-fluorophenyl)-3(R),5(S)-dihydroxy-8-(1-methyl-1H-tetrazol-5yl)-1-oxo-6,8-nonadien-1-yl]-L-leucine

When a solution of the compound from Example 147 in dioxane-water istreated at a temperature of about 0° C. with 1N NaOH and then acidifiedafter workup, the title compound is thereby produced.

EXAMPLE 150

The general procedure of Example 149 or Example 2 in U.S. Pat. No.4,678,806 is repeated, except that the compound from Example 147utilized therein is replaced by the compounds from Example 148, there isthereby produced

(a)N-[9,9-bis(4-fluorophenyl)-3(R),5(S)-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-1-oxo-6,8-nonadien-1-yl]-L-serine,

(b)N-[9,9-bis(4-fluorophenyl)-3(R),5(S)-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-1-oxo-6,8-nonadien-1-yl]-L-phenylalanineand

(c)N-[9,9-bis(4-fluorophenyl)-3(R),5(S)-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-1-oxo-6,8-nonadien-1-yl]-L-tyrosine.

What is claimed is:
 1. A compound of the formula ##STR61## wherein R¹and R⁴ each are independently hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, or trifluoromethyl;R²,R³,R⁵ and R⁶ each are independentlyhydrogen, halogen C₁₋₄ alkyl or C₁₋₄ alkoxy; tet is ##STR62## n is aninteger of from 0 to 2, inclusive; A is ##STR63## R⁷ is hydrogen, C₁₋₄alkyl, C₁₋₄ alkoxy(lower) alkyl or (2-methoxyethoxy)methyl; X is --OH or═O; and R⁸ is hydrogen, a hydrolyzable ester group or a cation to form anon-toxic pharmaceutically acceptable salt.
 2. A compound of claim 1having the formula ##STR64## wherein R¹ and R⁴ each are independentlyhydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl;R²,R³,R⁵and R⁶ each are independently hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄alkoxy; n is an integer of from 0 to 2 inclusive; A is ##STR65## R⁷ ishydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy(lower) alkyl or(2-methoxyethoxy)methyl; X is --OH or ═O; and R⁸ is hydrogen, ahydrolyzable ester group or a cation to form a non-toxicpharmaceutically acceptable salt.
 3. A compound of claim 2 wherein n=1.4. A compound of claim 3 having the formula ##STR66## whereinR¹,R²,R³,R⁴,R⁵, and R⁶ each are independently hydrogen, fluoro, chloro,methyl or methoxy;A is ##STR67## R⁷ is hydrogen or C₁₋₄ alkyl; and R⁸ ishydrogen, C₁₋₆ alkyl or a cation to form a non-toxic pharmaceuticallyacceptable salt.
 5. The compound of claim 1 which is ethylerythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate.6. The compound of claim 1 which iserythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt or hydrate thereof.7. The compound of claim 6 which is the (3R,5S) enantiomer of9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt or hydrate thereof.8. The compound of claim 6 which iserythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid monohydrate.
 9. The compound of claim 8 which is the (3R,5S)enantiomer of9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid monohydrate.
 10. The compound of claim 6 which is sodiumerythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate.11. The compound of claim 10 which is the (3R,5S) enantiomer of sodium9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate.12. The compound of claim 6 which is potassiumerythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate.13. The compound of claim 12 which is the (3R,5S) enantiomer ofpotassium9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoate.14. The compound of claim 1 which istrans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-2H-pyran-2-one.15. The compound of claim 14 which is the (4R,6S) enantiomer of6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.16. The compound of claim 1 which iserythro-11,11-bis(4-fluorophenyl)-3,5-dihydroxy-10-(1-methyl-1H-tetrazol-5-yl)-6,8,10-undecatrienoicacid or a non-toxic pharmaceutically acceptable salt.
 17. The compoundof claim 1 which istrans-6-[4,4-bis(4-fluorophenyl)-3-(2-methyl-2H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.18. The compound of claim 1 which iserythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(2-methyl-2H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 19. The compoundof claim 1 which is9,9-bis(4-fluorophenyl)-3-hydroxy-8-(1-methyl-1H-tetrazol-5-yl)-5-oxo-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 20. The compoundof claim 1 which iserythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 21. The compoundof claim 1 which is ethylerythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(1-methylethyl)-1H-tetrazol-5-yl]-6,8-nonadienoate.22. The compound of claim 1 which iserythro-9,9-bis(4-fluoro-3-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 23. The compoundof claim 1 which istrans-6-[4,4-bis(4-fluoro-3-methylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.24. The compound of claim 1 which iserythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-ethyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 25. The compoundof claim 1 which iserythro-9,9-bis(2,4-dimethylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 26. The compoundof claim 1 which iserythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-[1-(2-methoxyethoxy)-methyl-1H-tetrazol-5-yl]-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 27. The compoundof claim 1 which iserythro-9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 28. The compoundof claim 27 which is the (3R,5S) enantiomer of9,9-bis(4-fluoro-2-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 29. The compoundof claim 1 which istrans-6-[4,4-bis(4-fluoro-2-methylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.30. The compound of claim 29 which is the (4R,6S) enantiomer of6-[4,4-bis(4-fluoro-2-methylphenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.31. The compound of claim 1 which iserythro-9,9-bis(2-fluoro-4-methylphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 32. The compoundof claim 1 which iserythro-9-(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-9-phenylnona-6,8-dienoicacid or a non-toxic pharmaceutically acceptable salt.
 33. The compoundof claim 32 which is the (3R,5S) enantiomer of9-(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-9-phenylnona-6,8-dienoicacid or a non-toxic pharmaceutically acceptable salt.
 34. The compoundof claim 1 which istrans-6-[4-(4-fluorophenyl)-4-phenyl-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.35. The compound of claim 34 which is the (4R,6S) enantiomer of6-[4-(4-fluorophenyl)-4-phenyl-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one.36. The compound of claim 1 which iserythro-9,9-diphenyl-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 37. The compoundof claim 1 which iserythro-9,9-bis(4-methoxyphenyl)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-nonadienoicacid or a non-toxic pharmaceutically acceptable salt.
 38. A compound ofthe formula ##STR68## wherein R¹ and R⁴ each are independently hydrogen,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, or trifluoromethyl;R², R³, R⁵ and R⁶each are independently hydrogen, halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; R²⁰is hydrogen, C₁₋₆ alkyl or a metal cation and R²¹ is C₁₋₆ alkyl, hydroxyC₁₋₆ alkyl, phenyl C₁₋₆ alkyl, hydroxyphenyl C₁₋₆ alkyl, amido C₁₋₆alkyl, C₁₋₆ alkoxycarbonyl C₁₋₆ alkyl, imidazol-4-yl-C₁₋₆ alkyl, C₁₋₆alkylthio C₁₋₆ alkyl, or indol-3-yl C₁₋₆ alkyl in which the amido estermoiety is in the L-configuration.
 39. A compound of claim 38 wherein R²⁰is hydrogen, C₁₋₂ alkyl or a metal cation and R²¹ is C₁₋₄ alkyl, hydroxyC₁₋₂ alkyl, phenyl C₁₋₂ alkyl, hydroxyphenyl C₁₋₂ alkyl, amido C₁₋₂alkyl, C₁₋₂ alkoxycarbonyl C₁₋₂ alkyl, imidazol-4-yl C₁₋₂ alkyl, C₁₋₂alkylthio C₁₋₂ alkyl or indol-3-yl C₁₋₂ alkyl in which the amido estermoiety is in the L-configuration.
 40. A compound of claim 39 wherein R²¹is C₁₋₄ alkyl, hydroxymethyl, phenylmethyl or hydroxyphenyl-methyl inwhich the amido ester moiety is in the L-configuration.